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Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.
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ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2
Rule Set: | |
|---|---|
Disease(s) |
hypercholesterolemia, familial, 1
|
Gene(s) | LDLR |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | See PVS1 flow diagram (Figure 1). |
| PVS1 - Strong | See PVS1 flow diagram (Figure 1). |
| PVS1 - Moderate | See PVS1 flow diagram (Figure 1). |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change. Caveat: there is no in silico predicted splicing impact for either variant. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | Variant is de novo in a patient with the disease and no family history. Follow SVI guidance for de novo occurrences: https://clinicalgenome.org/working-groups/sequence-variant-interpretation/ |
Showing 1 to 10 of 107 entries
ClinGen Cardiomyopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1
Rule Set: | |
|---|---|
Disease(s) |
NA
|
Gene(s) | MYH7 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | NA |
| PVS1 - Strong | NA |
| PVS1 - Moderate | Null Variant in gene with evidence supporting LOF as disease mechanism |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Different nucleotide change (same amino acid) as a previously established pathogenic variant |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | De novo (paternity confirmed) in a patient with disease and no family history |
Showing 1 to 10 of 107 entries
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.1.0
Rule Set: | |
|---|---|
Disease(s) |
NA
|
Gene(s) | PTEN |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use PTEN PVS1 decision tree. |
| PVS1 - Strong | Use PTEN PVS1 decision tree. |
| PVS1 - Moderate | Use PTEN PVS1 decision tree. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change OR different variant at same nucleotide position as a pathogenic splicing variant, where in silico models predict impact equal to or greater than the known pathogenic variant. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history. |
| PS2 - Strong | De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. |
Showing 1 to 10 of 107 entries
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1
Rule Set: | |
|---|---|
Disease(s) |
NA
|
Gene(s) | SHOC2, NRAS, RAF1, SOS1, SOS2, PTPN11, KRAS, MAP2K1, HRAS, RIT1, MAP2K2, BRAF |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment. |
| PVS1 - Strong | Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment. |
| PVS1 - Moderate | Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment. |
| PVS1 - Supporting | Not Applicable: LOF and/or haploinsufficiency has not been clearly identified as disease mechanisms for these genes relative to the RASopathy spectrum phenotype, therefore in general this rule is not applicable. Note that PTPN11 is currently the only gene with a confirmed association to another non-RASopathy disorder due to LOF alleles. Variants in PTPN11 with predicted LOF should not be evaluated by these RASopathy specific criteria, but should defer to non-adjusted criteria. Given that some historical LOF variants (e.g. canonical splice sites) could potentially result in a gain of function, users should assess using these criteria and non-adjusted criteria to identify the highest likelihood of pathogenicity for all associated diseases. We recommend that the ClinGen Dosage Sensitivity Map Status (http://www.ncbi.nlm.nih.gov/projects/dbvar/clingen/index.shtml) be reviewed for any new apparently LOF disease associations prior to classification assessment. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Previously established variant must be established as pathogenic per these criteria for germline RASopathy variants. This evidence rule can also be applied for the any observed analogous residue positions/regions throughout the gene in highly analogous groupings below: Group 1: HRAS, NRAS, KRAS Group 2: MAP2K1, MAP2K2 Group 3: SOS1, SOS2 |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | ≥2 independent occurrences of PS2 OR ≥2 independent occurrences of PM6 and one occurrence of PS2. Evidence from literature must be fully evaluated to support independent events. |
| PS2 - Strong | De novo (paternity confirmed) in a patient with the disease and no family history. |
Showing 1 to 10 of 107 entries
ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2
Rule Set: | |
|---|---|
Disease(s) |
Usher syndrome, nonsyndromic genetic hearing loss, Pendred syndrome
|
Gene(s) | CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA, USH2A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications. |
| PVS1 - Strong | See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease. • PVS1 should also be considered for the following genes with variants assessed in the Hearing Loss Variant Pilot: GJB2, CDH23, USH2A, SLC26A4, MYO6, MYO7A, TECTA, KCNQ4. • For other genes, LOF must be an established disease mechanism, and the gene/disease association must be Strong or Definitive clinical validity level as outlined in Strande et al. 2017 (PMID: 28552198). • If above criteria is met, follow PVS1 flowchart as recommended by the SVI. |
| PVS1 - Moderate | See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease. |
| PVS1 - Supporting | See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant. • Established variant must meet criteria for pathogenicity by the HL specifications • Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant • Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T • No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen. • Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change) |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | 4 points per tables 5a and 5b: Examples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR 4 assumed de novo occurrences. |
| PS2 - Strong | 2 points per tables 5a and 5b: Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences. |
Showing 1 to 10 of 107 entries
Rule Set: | |
|---|---|
Disease(s) |
phenylketonuria
|
Gene(s) | PAH |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. |
| PVS1 - Strong | NA |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | De novo (paternity confirmed) in a patient with the disease and no family history. |
Showing 1 to 10 of 107 entries
ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1
Rule Set: | |
|---|---|
Disease(s) |
hereditary diffuse gastric adenocarcinoma
|
Gene(s) | CDH1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Per modified CDH1 PVS1 decision tree. |
| PVS1 - Strong | Per modified CDH1 PVS1 decision tree. Other CDH1 caveats: • Use PVS1_Strong as the default strength of evidence for canonical splice site variants and follow the site-specific recommendations in the splicing table. • CDH1 Exonic deletions or tandem duplications of in-frame exons (exon 4,5,8,9,12,13,15). |
| PVS1 - Moderate | Per modified CDH1 PVS1 decision tree. Other CDH1 caveats: • G to non-G variants disrupting the last nucleotide of an exon. • Canonical splice sites predicted or demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site). |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | Not Applicable: Not applicable for CDH1. |
| PS1 - Strong | Not Applicable: Not applicable for CDH1. |
| PS1 - Moderate | Not Applicable: Not applicable for CDH1. |
| PS1 - Supporting | Not Applicable: Not applicable for CDH1. |
| PS2 - Very Strong | ≥Two patients meet the HDGC individual phenotype criteria w/ parental confirmation. |
| PS2 - Strong | One patient meets the HDGC individual phenotype criteria w/ parental confirmation. |
Showing 1 to 10 of 107 entries
ClinGen Myeloid Malignancy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2
Rule Set: | |
|---|---|
Disease(s) |
hereditary thrombocytopenia and hematologic cancer predisposition syndrome
|
Gene(s) | RUNX1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. |
| PVS1 - Strong | Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. |
| PVS1 - Moderate | Per modified RUNX1 PVS1 decision tree for SNVs and CNVs and table of splicing effects. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | NA |
Showing 1 to 10 of 107 entries
ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TP53 Version 1.4.0
Rule Set: | |
|---|---|
Disease(s) |
Li-Fraumeni syndrome
|
Gene(s) | TP53 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Defer to SVI recommendations |
| PVS1 - Strong | NA |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Must confirm there is no difference in splicing using RNA data. Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. |
| PS1 - Moderate | Must confirm there is no difference in splicing using in silico modeling data using a splice metapredictor (SpliceAI, VarSEAK, etc). Can only compare to variants asserted as pathogenic by the ClinGen TP53 EP. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document. ≥4 points (ex. – 2 cancers in two probands from the strong criteria list or 4 cancers from 4 probands from the moderate criteria). For probands with multiple cancers, use the most specific/highest weight cancer to determine point for that proband. |
| PS2 - Strong | Use SVI point system table. See Cancer Criteria List & TP53 Point Table at end of document. 2-3 points (ex. – 1 cancer from the strong criteria list or 2 from the moderate criteria list) |
Showing 1 to 10 of 107 entries
ClinGen Lysosomal Storage Disorders Variant Curation Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2
Rule Set: | |
|---|---|
Disease(s) |
glycogen storage disease II
|
Gene(s) | GAA |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease or in frame loss of an exon that contains residues involved in the active site of GAA. • Any nonsense, frameshift, or splice variant creating a premature stop codon before codon 916. • In frame deletions of an entire exon containing critical active site/substrate binding residues (exons 8 and 10), or for which another variant removing the exon is known to be pathogenic (exons 2 and 18). |
| PVS1 - Strong | Null variant in a gene where loss of function is a known mechanism of disease. • In frame loss of an exon which is part of the catalytic barrel domain and contains pathogenic/likely pathogenic nontruncating variants (exons 6 and 9). • Initiator codon variant. |
| PVS1 - Moderate | Null variant in a gene where loss of function is a known mechanism of disease. • Premature termination codon in the 3’ end of GAA (3’ to codon 916), not predicted to be detected by nonsense-mediated decay. • Predicted exon-skipping due to canonical splice variant or exon deletion resulting in an in frame deletion of <10% of the gene product (exons 17, 19, and 20). |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Not Applicable: De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines. |
| PS2 - Strong | Not Applicable: De novo variants are rarely reported in GAA (PMIDs 7981676, 27142047). The occurrence of de novo variants in GAA is not a mechanism of disease for Pompe disease, and the observation that a variant in GAA has arisen de novo does not support its causality. Any de novo variants will be assessed based on the variant type, functional evidence, and in trans data as described in these guidelines. |
Showing 1 to 10 of 107 entries
ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1
Rule Set: | |
|---|---|
Disease(s) |
Glanzmann thrombasthenia
|
Gene(s) | ITGA2B, ITGB3 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use decision tree as per SVI WG with specified “regions critical to protein function”. |
| PVS1 - Strong | NA |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Use with no specification. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | Use proposed SVI point recommendations. • Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant |
Showing 1 to 10 of 107 entries
ClinGen Malignant Hyperthermia Susceptibility Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RYR1 Version 2
Rule Set: | |
|---|---|
Disease(s) |
malignant hyperthermia of anesthesia
|
Gene(s) | RYR1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1. |
| PVS1 - Strong | Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1. |
| PVS1 - Moderate | Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1. |
| PVS1 - Supporting | Not Applicable: PVS1 is not applicable. MHS is due to gain of function variants in RYR1. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change • Previously established pathogenic variant must reach a classification of pathogenic without PS1 |
| PS1 - Moderate | Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. • Previously established likely pathogenic variant must reach a classification of likely pathogenic without PS1. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Each proven de novo case, 2 points, each assumed de novo case, 1 point, ≥8 points |
| PS2 - Strong | Each proven de novo case, 2 points, each assumed de novo case, 1 point, a total of 4-7 points |
Showing 1 to 10 of 107 entries
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_ntDNA
Rule Set: | ||||
|---|---|---|---|---|
Disease(s) |
biotin-responsive basal ganglia disease
|
pyruvate dehydrogenase deficiency
|
mitochondrial disease
|
ethylmalonic encephalopathy
|
Gene(s) | SLC19A3 | PDHA1 | POLG | ETHE1 |
Genetype | nuclear | nuclear | nuclear | nuclear |
Criteria Code | Strength Specification | Strength Specification | Strength Specification | Strength Specification |
| PVS1 - Very Strong | Applied per PVS1 flowsheet of Abou Toyoun et al. | Applied per PVS1 flowsheet of Abou Toyoun et al. | Applied per PVS1 flowsheet of Abou Toyoun et al. | Applied per PVS1 flowsheet of Abou Toyoun et al. |
| PVS1 - Strong | NA | NA | NA | NA |
| PVS1 - Moderate | NA | NA | NA | NA |
| PVS1 - Supporting | NA | NA | NA | NA |
| PS1 - Very Strong | NA | NA | NA | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change |
| PS1 - Moderate | NA | NA | NA | NA |
| PS1 - Supporting | NA | NA | NA | NA |
| PS2 - Very Strong | NA | NA | NA | NA |
| PS2 - Strong | De novo in a patient with the disease and no family history | De novo in a patient with the disease and no family history | De novo in a patient with the disease and no family history | De novo in a patient with the disease and no family history |
Showing 1 to 10 of 107 entries
ClinGen Mitochondrial Disease Nuclear and Mitochondrial Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1_mtDNA
Rule Set: | |
|---|---|
Disease(s) |
NA
|
Gene(s) | NA |
Genetype | mitochondrial |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Large heteroplasmic mtDNA deletions, where at least one gene is completely deleted |
| PVS1 - Strong | Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018) |
| PVS1 - Moderate | Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018) |
| PVS1 - Supporting | Assessment of small deletions, nonsense, and frameshift variants in protein-coding genes should follow established guidelines (Abou Tayoun et al., 2018) |
| PS1 - Very Strong | NA |
| PS1 - Strong | Applied per original ACMG/AMP guidelines |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance |
| PS2 - Strong | De novo (maternity confirmed or identical full mtDNA sequence) in a patient with the disease and no family history; with weighting per ClinGen SVI guidance |
Showing 1 to 10 of 107 entries
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PALB2 Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
hereditary breast carcinoma, familial pancreatic carcinoma, Fanconi anemia complementation group N
|
Gene(s) | PALB2 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use PALB2 PVS1 Decision Tree |
| PVS1 - Strong | Use PALB2 PVS1 Decision Tree. |
| PVS1 - Moderate | Use PALB2 PVS1 Decision Tree. |
| PVS1 - Supporting | Use PALB2 PVS1 Decision Tree |
| PS1 - Very Strong | NA |
| PS1 - Strong | Use PALB2 PS1 Splicing table |
| PS1 - Moderate | Use PALB2 PS1 Splicing table |
| PS1 - Supporting | Use PALB2 PS1 Splicing table |
| PS2 - Very Strong | Not Applicable: ● Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase ● Autosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified. ● Autosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies. |
| PS2 - Strong | Not Applicable: ● Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase ● Autosomal Dominant Disease: Do not use-Informative de novo occurrences have not yet been observed for autosomal dominant disease. As breast cancer is relatively common and occurs frequently as an apparently sporadic event, de novo is unlikely to ever be informative unless specific features of PALB2-related cancer predisposition are identified. ● Autosomal Recessive Disease: Do not use - de novo occurrences are too rare to be informative at this time. In addition, in a biallelic state, de novo occurrences have an exceedingly low probability of being able to be confirmed as in trans because parental testing (and identification of one variant in each parent) is typically required without the use of long-range technologies. |
Showing 1 to 10 of 107 entries
ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
NA
|
Gene(s) | VHL |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **LINK TO PVS1 DECISION TREE DOCUMENT:* • [**https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing**](https://drive.google.com/file/d/1mGfChgxbGVbzYn6Ggmb9rYvoGGah25ll/view?usp=sharing) **Do not apply PVS1 for truncations that occur prior to Codon 54 (including frameshift events that start and end prior to Codon 54 but the truncation extends beyond Codon 54.)** **Note1: Exon presence in biologically relevant transcripts:* • In some transcripts exon 2 of _VHL_ is skipped and expressed at low levels. The function of this transcript is not fully known. Exon 2 comprises almost the entirety of the nuclear export function region of the Beta domain and is critical for known VHL function. Exon 1 contains the only initiator codons in _VHL_. Exon 3 contains the elongin binding function. _**All exons should be considered as "present in biologically relevant transcripts" in the PVS1 decision tree.**_ **Note 2: The 10% PVS1 downgrade to Moderate cannot apply to VHL* • because of the small size. **Nonsense Mediated Decay* • [5](#pmid_22825683) [4](#pmid_20145706) **NMD experimental evidence in 1st exon after codon 54 and to 5' region of 2nd exon (codon 138)**.\*\* **Critical Domains:** 1st Beta (β) domain (63-154), especially Nuclear Export (114-155) Alpha (ɑ) domain (155-192), especially Elongin C binding (157 - 172) Second Beta domain (193-204) _Truncating variants after Met54 and predicted to undergo NMD (from AA55-AA136/c.408) or in the beta or alpha domains can receive PVS1, and those outside the second Beta domain (205-213) can receive PVS1\_Moderate downgrade to account for minimal loss of VHL protein. Notably a frame shift deletion at 205 is pathogenic in ClinVar (ID 18971) as are stop loss extension variants in the last codons (see PM4)._ **SPLICE: If any canonical exon is skipped, the variant receives PVS1.* • If a cryptic splice disrupts the reading frame, and is in a critical domain (AA63-AA204) or is predicted to undergo NMD (AA55-AA136) it receives PVS1. If it is outside a critical domain and predicted to undergo NMD (AA55-62), it receives PVS1\_Strong (the second site outside of critical domains AA205-213 is not predicted to undergo NMD). If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1\_Strong, and if it is outside the critical domain (AA 205-213) or in an NMD prediction (AA 55-62), it receives PVS1\_Moderate. Note: There is a cryptic exon (E1) in intron 1 [7](#pmid_31996412) [6](#pmid_29891534), and silent variants in exon 2 that are reported to cause skipping of exon 1. If there is functional evidence of exon skipping (RNA splice assay) then PVS1 can apply. Do not double count evidence. Ex. PVS1 should be used in place of PS3 functional evidence confirming splice alteration, but PS3 evidence code could still apply to other relevant assays confirming effect on HIF1/2a presence etc. **EXON DELETION:* • SVI PVS1 decision tree modified for whole exon deletions. There are only 3 exons in _VHL_ and each has an important functional domain. Any exon deletion of _VHL_ receives PVS1. **EXON DUPLICATION:* • Follow PVS1 decision tree. Note: few pathogenic exon duplications are reported in ClinVar. (ID:417571, ID:584137). These have no literature cited. **INITIATION CODON:* • VHL Met 1 (in VHL p30) truncation or missense would not affect VHL p19, as VHL has a second start at codon 54 (VHL p19), it cannot be scored in the PVS1 decision tree. After that, no other viable alternative starts are known. Start loss at codon 54 would presumably result in an impact, as VHL p30 and p19 would be truncated prior to any known functional domains (PVS1). Ong 2007 has 1 family (2 subjects) with Met54X and reports cerebellar hemangioblastomas. There is no functional study in the paper for this variant. Olschwang et al 1998 VHL Type 2A, one subject with 161insT (FS result). There is no functional study in the paper. Missense at Met 54 (VHL p19 initiation codon) would presumably not result in as strong an impact as the full length VHL p30 would still be produced (PVS1 decision tree = N/A). ClinVar has M54T (ID:819688) and M54L (ID:843990). M54T is uncertain, with no other evidence provided. M54L references M54I which segregates in homozygous state with erythrocytosis in individuals of Moroccan descent [9](#pmid_26224408) [8](#pmid_27578599), and those heterozygous for M54I did not present VHL phenotype [9](#pmid_26224408). |
| PVS1 - Strong | NA |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Applied only to variants with interpretation by the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | A single proband cannot be very strong evidence, but multiple probands can be combined to reach very strong (4+ points). |
| PS2 - Strong | Phenotype highly specific for the gene (Danish Criteria) (≥2 but less than 4 _de novo_ points). |
Showing 1 to 10 of 107 entries
ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
hemophilia B
|
Gene(s) | F9 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree. |
| PVS1 - Strong | Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree. |
| PVS1 - Moderate | Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree. |
| PVS1 - Supporting | Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree. |
| PS1 - Very Strong | NA |
| PS1 - Strong | This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect. |
| PS1 - Moderate | This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on _F9_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value. |
| PS2 - Strong | Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value. |
Showing 1 to 10 of 107 entries
ClinGen Thrombosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SERPINC1 Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
hereditary antithrombin deficiency
|
Gene(s) | SERPINC1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use decision tree as per SVI WG with specified “regions critical to protein function”. |
| PVS1 - Strong | Use decision tree as per SVI WG with specified “regions critical to protein function”. |
| PVS1 - Moderate | Use decision tree as per SVI WG with specified “regions critical to protein function”. |
| PVS1 - Supporting | Use decision tree as per SVI WG with specified “regions critical to protein function”. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Use with no specification except comparison variant must be classified as pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP. |
| PS1 - Moderate | Use with no specification except comparison variant must be classified as likely pathogenic using _SERPINC1_ rule specifications from the Thrombosis VCEP. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 4 points. |
| PS2 - Strong | Use proposed SVI point recommendations for “Phenotype highly specific for gene.” See de novo rule code guidance attached. Required 2 points. |
Showing 1 to 10 of 107 entries
ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF4A Version 2.0.0
Rule Set: | |
|---|---|
Disease(s) |
monogenic diabetes
|
Gene(s) | HNF4A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use _HNF4A_ PVS1 decision tree. • Variants generating PTCs in exon 10 and last 55 nucleotides of exon 9 (c.1162-1216) are not expected to cause NMD[1](#pmid_24274751) • The most 3’ nonsense or frameshift variant is c.1256C>G, p.S419X in the last exon. This variant has been classified as Pathogenic by the MDEP. There are six other nonsense and frameshift variants in exon 10, none of which have case information and are all currently classified as VUS. The collective evidence supports applying PVS1 for variants at codon 419 (c.1257) and 5’ and PVS1\_Supporting for variants at c.1258 (G)/p.Gly420 and 3’. • “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” • Exons 1, 2 (LRG 4), 3 (LRG 5), 4 (LRG 6), 6 (LRG 8): deletion or skipping causes frameshift: PVS1 • Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\_Strong • Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\_Strong |
| PVS1 - Strong | Use _HNF4A_ PVS1 decision tree. • “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” • Exons 5 (LRG 7), 7 (LRG 9), 8 (LRG 10), 9 (LRG 11) - deletion or skipping causes in-frame deletion, 52/52/79/51-79 AA deleted, that is >10 % of the protein in each case - PVS1\_Strong • Exon 10 (LRG 12) - 46 AA, contains the transactivation domain, includes stop loss - PVS1\_Strong • Apply PVS1\_Strong to initiation codon variants. MDEP has classified two start codon variants as likely pathogenic (c.3G>A: PM2\_Supporting + PP4\_Moderate + PP1\_Strong + PVS1\_Moderate (c.1delA); c.1delA: PM2\_Supporting + PP1 + PP4\_Moderate + PVS1\_Moderate) and there are multiple P/LP variants before the next methionine, p.Met71. |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | Use _HNF4A_ PVS1 decision tree. Apply PVS1\_Supporting to nonsense or frameshift variants at c.1258 (G)/p.Gly420 and 3’. |
| PS1 - Very Strong | NA |
| PS1 - Strong | No change |
| PS1 - Moderate | NA |
| PS1 - Supporting | PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact. |
| PS2 - Very Strong | Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions. |
| PS2 - Strong | Use SVI recommended point-based system with specifications for “Phenotype Consistency” per instructions. |
Showing 1 to 10 of 107 entries
ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0
Rule Set: | |
|---|---|
Disease(s) |
monogenic diabetes
|
Gene(s) | GCK |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use _GCK_ PVS1 decision tree created based on PVS1 decision tree from ClinGen SVI group[1](#pmid_30096381) • Variants generating PTCs 3’ of c.1198 (p.Asp400) of NM\_000162.3, which includes the last 55 nucleotides of exon 9 and exon 10, are not expected to cause NMD[2](#pmid_24274751). The α13 helix (p.444-456), located at the C-end of the protein, has a critical role in GCK conformational change upon glucose binding. Individuals with PTCs in exon 10 have a MODY phenotype. Therefore, a “very strong” level of evidence will be applied for PTCs in exon 10. • “Exon skipping or “use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” • single exon deletions • deletion of exon 1 is in-frame but over 20 families with GCK-MODY phenotype and exon 1 deletion (some also have promoter deletions) --> PVS1 • deletions of single **exons 2,3,6 and 7* • cause frameshift --> **PVS1** • deletions or skipping of **exons 8 and 9* • are in-frame and the proportion is >10 % (52 AA and 78 AA, respectively) --> **PVS1** • deletions or skipping of **exons 4 and 5* • are in-frame and the proportion is \<10 % (40 AA and 32 AA, respectively). Exon 4 (p.122-161) and exon 5 (p.162-193) contain each a part of the active site that binds glucose /p.151-180[3](#pmid_23957911) according to Beck et al., Biochemistry 2013/ --> **PVS1** • deletion of exon 10 (47 AA) – There are a number of patients with a GCK-MODY phenotype with reported with missense, frameshift, PTC, splice acceptor, and stop loss variants in exon 10 --> **PVS1** • Apply PVS1\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\_Supporting + PM2\_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. • Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1. |
| PVS1 - Strong | Use _GCK_ PVS1 decision tree. Per the SVI standard PVS1 decision tree, apply PVS1\_Strong to duplications ≥ 1 exon in size, contained completely within gene, proven not in tandem, reading frame presumed disrupted, and NMD predicted to occur. |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | Use _GCK_ PVS1 decision tree. • Apply PVS1\_Supporting to initiation codon variants given MDEP has only reviewed one variant and classified as VUS (c.3G>A, PVS1\_Supporting + PM2\_Supporting; one case submitted, dx.53 and no other info provided to lab). The next methionine is at codon 8 and there are no variants classified as pathogenic 5' of p.Met8. • Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1. |
| PS1 - Very Strong | NA |
| PS1 - Strong | No change |
| PS1 - Moderate | NA |
| PS1 - Supporting | PS1 may be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact. |
| PS2 - Very Strong | Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. . |
| PS2 - Strong | Use SVI-recommended point-based system with specifications for “Phenotype Consistency” per instructions. |
Showing 1 to 10 of 107 entries
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0
Rule Set: | |
|---|---|
Disease(s) |
familial adenomatous polyposis 1
|
Gene(s) | APC |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \[Reference 1\]. |
| PVS1 - Strong | Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \[Reference 1\]. |
| PVS1 - Moderate | Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \[Reference 1\]. |
| PVS1 - Supporting | Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (**Figure 1**) \[Reference 1\]. |
| PS1 - Very Strong | NA |
| PS1 - Strong | The previously established variant was classified as Pathogenic according to the APC-specific modifications. This criterion can be applied to both missense and splice variants in _APC_. **Missense variants:* • when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. **Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors. |
| PS1 - Moderate | The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications. This criterion can be applied to both missense and splice variants in _APC_. **Missense variants:* • when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1\_Moderate. No missense variant has been classified as Pathogenic based on current evidence. **Splice variants**: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple _in silico_ predictors. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | ≥ 4 _de novo_ scores. For curation of _de novo_ score see **Tables 1* • and **2**. |
| PS2 - Strong | 2-3.5 _de novo_ scores. For curation of _de novo_ score see **Tables 1* • and **2**. |
Showing 1 to 10 of 107 entries
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
breast-ovarian cancer, familial, susceptibility to, 1
|
Gene(s) | BRCA1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PVS1 - Strong | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PVS1 - Moderate | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PVS1 - Supporting | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Apply **PS1**, for predicted **missense* • substitutions, where a previously classified **pathogenic* • variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). Apply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **pathogenic* • variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. See Specifications Table 5 and Appendix E, J and K for details. |
| PS1 - Moderate | Apply **PS1\_Moderate**, for predicted **missense* • substitutions, where previously classified **likely pathogenic* • variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). Apply **PS1\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic* • variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. See Specifications Table 5 and Appendix E, J and K for details. |
| PS1 - Supporting | Apply **PS1\_Supporting**, for exonic and intronic variants with same predicted impact on **splicing,* • as a previously classified **(likely) pathogenic* • variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. See Specifications Table 5 and Appendix E, J and K for details. |
| PS2 - Very Strong | Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences. |
| PS2 - Strong | Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences. |
Showing 1 to 10 of 107 entries
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
breast-ovarian cancer, familial, susceptibility to, 2
|
Gene(s) | BRCA2 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PVS1 - Strong | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PVS1 - Moderate | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PVS1 - Supporting | Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Apply at appropriate strength according to PVS1 flowchart, which considers knowledge of clinically important functional domains. See Specifications Table 4 and Appendix D for details. Well-established _in vitro_ or _in vivo_ functional studies supportive of a damaging effect _as measured by effect on mRNA transcript profile (mRNA assay only)._ Apply as PVS1 (RNA) at appropriate strength. See Specifications Figure1B and Appendix E for details. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Apply **PS1**, for predicted **missense* • substitutions, where a previously classified **pathogenic* • variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). Apply **PS1**, for exonic and intronic variants with same predicted impact on **splicing,* • as a previously classified **pathogenic* • variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. See Specifications Table 5 and Appendix E, J and K for details. |
| PS1 - Moderate | Apply **PS1\_Moderate**, for predicted **missense* • substitutions, where a previously classified **likely pathogenic* • variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). Apply **PS1\_Moderate**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic* • variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. See Specifications Table 5 and Appendix E, J and K for details. |
| PS1 - Supporting | Apply **PS1**, for exonic and intronic variants with same predicted impact on **splicing**, as a previously classified **(likely) pathogenic* • variant. Vary weight depending on relative positions, and confidence in classification of the reference variant. See Specifications Table 5 and Appendix E, J and K for details. |
| PS2 - Very Strong | Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences. |
| PS2 - Strong | Not Applicable: BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences. |
Showing 1 to 10 of 107 entries
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ADA Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
|
Gene(s) | ADA |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)). |
| PVS1 - Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 12, or variants in the last 50 nucleotides of the penultimate exon after c.1028, codon 343, in exon 11), at least one pathogenic variant **must be* • present downstream in order to apply PVS1\_Strong. |
| PVS1 - Moderate | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 12, or variants in the last 50 nucleotides of the penultimate exon after c.1028, codon 343, in exon 11), when at least one pathogenic variant is **not* • present downstream downgrade to PVS1\_Moderate. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as **pathogenic* • by SCID VCEP specifications for _ADA._ |
| PS1 - Moderate | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as **likely pathogenic* • by SCID VCEP specifications for _ADA._ |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
| PS2 - Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
Showing 1 to 10 of 107 entries
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DCLRE1C Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
severe combined immunodeficiency due to DCLRE1C deficiency
|
Gene(s) | DCLRE1C |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)). |
| PVS1 - Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 14, or variants in the last 50 nucleotides of the penultimate exon after c.1106, codon 369, in exon 13), at least one pathogenic variant **must be* • present downstream in order to apply PVS1\_Strong. _Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)._ |
| PVS1 - Moderate | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 14, or variants in the last 50 nucleotides of the penultimate exon after c.1106, codon 369, in exon 13), when at least one pathogenic variant is **not* • present downstream downgrade to PVS1\_Moderate. _Note: Exons 1-3 and exons 1-4 have been reported as a hot spot for deletion variants as a result of homologous recombination of the wild-type DCLRE1C gene with a DCLRE1C pseudogene (PMID: 19953608)._ |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as **pathogenic* • by SCID VCEP specifications for _DCLRE1C._ |
| PS1 - Moderate | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as **likely pathogenic* • by SCID VCEP specifications for _DCLRE1C._ |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
| PS2 - Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
Showing 1 to 10 of 107 entries
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL7R Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
immunodeficiency 104
|
Gene(s) | IL7R |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)). |
| PVS1 - Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.826, codon 276, in exon 7), at least one pathogenic variant **must be* • present downstream in order to apply PVS1\_Strong. • PVS1\_Strong can be applied to variants not predicted to undergo nonsense-mediated decay but causing truncation of the transmembrane domain (which begins at amino acid 240) or any distal region (i.e. cytoplasmatic domain). |
| PVS1 - Moderate | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.826, codon 276, in exon 7), when at least one pathogenic variant is **not* • present downstream downgrade to PVS1\_Moderate. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as **pathogenic* • by SCID VCEP specifications for _IL7R._ |
| PS1 - Moderate | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as **likely pathogenic* • by SCID VCEP specifications for _IL7R._ |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
| PS2 - Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
Showing 1 to 10 of 107 entries
ClinGen Leber Congenital Amaurosis/early onset Retinal Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPE65 Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
RPE65-related recessive retinopathy
|
Gene(s) | RPE65 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group [16](#pmid_30192042) and as updated by the ClinGen SVI Splicing Subgroup [17](#pmid_37352859) • Refer to RPE65-specific PVS1 Decision Tree, file attached. • PVS1: Predicted splice defects at +/- 1,2 in exons 1-14 • PVS1: Single to multi-exon deletions, with or without predicted NMD. All exons are considered critical to protein function. • PVS1: Nonsense or frameshift mutations from p.Ser2 through p.Gly528 • PVS1: Duplications of exons proven in tandem • PVS1(RNA): RNA splicing data with evidence of alternative transcript production at complete levels, relative to normal allele. |
| PVS1 - Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group [16](#pmid_30192042) and as updated by the ClinGen SVI Splicing Subgroup [17](#pmid_37352859) • Refer to RPE65-specific PVS1 Decision Tree, file attached. • PVS1\_Strong:Applied to variants in the initiation codon. The second in-frame methionine is located at residue 93, and there is no known study indicating that this methionine in _RPE65_ can be used as start codon. Variants affecting Met1 can lead to a complete absence of the protein product. Even though we cannot exclude the possibility of a 2nd Met being used as start codon, the translation efficiency maybe significantly reduced due to lack of other important elements (Kozak sequence, etc.). Also, there are multiple variants located upstream of Met93 having been reported as a pathogenic variant in HGMD and ClinVar, evidence that this region of the protein is functionally important. • PVS1\_Strong: Nonsense or frameshift mutations from p.Leu529 through p.Ser533 • PVS1\_Strong: Duplications of exons presumed in tandem • PVS1(RNA)\_Strong: RNA splicing data with evidence of alternative transcript production at near complete levels, relative to normal allele. |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established Pathogenic variant regardless of nucleotide change. • Must have one comparison variant that reaches a Pathogenic classification using this rule specification. • For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other. Same predicted splicing impact as a previously classified Pathogenic variant. • Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the **same position* • that has been designated **Pathogenic**. • Used in conjunction with PVS1 for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and that have a comparable variant within the same splice donor/acceptor +/-1,2 dinucleotide that has been designated Pathogenic. Specific combinations are found in RPE65-specific PVS1 Decision Tree **part (b)* • (Table 2 from Walker 2023). |
| PS1 - Moderate | Same amino acid change as a previously established Likely Pathogenic variant regardless of nucleotide change. • Must have one comparison variant that reaches a Likely Pathogenic classification using this rule specification. • For assessing same amino acid changes, SpliceAI scores for both variants should be within 10% of each other. Same predicted splicing impact as previously classified Likely Pathogenic variant. • Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant at the **same position* • that has been designated **Likely Pathogenic**. • Used in conjunction with PVS1\_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable variant **within the same splice donor/acceptor motif* • (but outside the +/-1,2 dinucleotide) that has been designated **Pathogenic**. Specific combinations are found in RPE65-specific PVS1 Decision Tree **part (b)* • (Table 2 from Walker 2023). |
| PS1 - Supporting | • Used in conjunction with PP3 for variants located outside the splice donor/acceptor +/-1,2 dinucleotide positions that have a splice AI score ≥0.2 and have a comparable nucleotide variant within the **same motif* • that has been designated **Likely Pathogenic**. • Used in conjunction with PVS1 or PVS1\_(reduced strength) for variants located at the splice donor/acceptor +/-1,2 dinucleotide positions and have a comparable Likely Pathogenic or Pathogenic variant either within the same splice site donor/acceptor motif, outside the +/-1,2 dinucleotide, or at the +/-1,2 dinucleotide. Specific combinations are found in RPE65-specific PVS1 Decision Tree **part (b)* • (Table 2 from Walker 2023). |
| PS2 - Very Strong | De novo (**both* • maternity and paternity confirmed) in a patient with the disease and no family history. • Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband) • Total of 4 or more points required for Very Strong level |
| PS2 - Strong | De novo (**both* • maternity and paternity confirmed) in a patient with the disease and no family history. • Use ClinGen SVI's recommendation for assigning weight to the PS2/PM6 codes (See PS2-Table 1 within PS2/PM6 file). Use option 3 “Phenotype consistent with gene but not highly specific and high genetic heterogeneity” (maximum 0.5 points/proband) • Total of 2.00 - 3.75 points required for Strong level |
Showing 1 to 10 of 107 entries
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for JAK3 Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
T-B+ severe combined immunodeficiency due to JAK3 deficiency
|
Gene(s) | JAK3 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)). |
| PVS1 - Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), at least one pathogenic variant **must be* • present downstream in order to apply PVS1\_Strong. |
| PVS1 - Moderate | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 24, or variants in the last 50 nucleotides of the penultimate exon after c.3157, codon 1053, in exon 23), when at least one pathogenic variant is **not* • present downstream downgrade to PVS1\_Moderate. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as **pathogenic* • by SCID VCEP specifications for _JAK3._ |
| PS1 - Moderate | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as **likely pathogenic* • by SCID VCEP specifications for _JAK3._ |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
| PS2 - Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
Showing 1 to 10 of 107 entries
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG1 Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
recombinase activating gene 1 deficiency
|
Gene(s) | RAG1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications: • Given that the _RAG1_ protein is encoded by a single exon (based on MANE Select transcript NM\_000448.3) and nonsense-mediated decay is not predicted for nonsense or frameshift variants, PVS1 cannot be applied at the default strength to RAG1 variants (indicated by the red boxes in the Flowchart attached), **except* • in the case of full gene deletion **or* • removing/altering critical domain for the protein (NBD domain, DDBD domain, and core domain, indicated by the purple in the Flowchart). • PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay when removing/altering the critical NBD domain (aa 394-460), DDBD domain (aa 461-517), and core domain (aa 387-1011) based on recommendations from Walker et al., preprint. |
| PVS1 - Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, at least one pathogenic variant **must be* • present downstream in order to apply PVS1\_Strong. |
| PVS1 - Moderate | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, when at least one pathogenic variant is **not* • present downstream, downgrade to PVS1\_Moderate. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as **pathogenic* • by SCID VCEP specifications for _RAG1._ |
| PS1 - Moderate | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as **likely pathogenic* • by SCID VCEP specifications for _RAG1._ |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
| PS2 - Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
Showing 1 to 10 of 107 entries
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAG2 Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
recombinase activating gene 2 deficiency
|
Gene(s) | RAG2 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with two specifications: • Given that the _RAG2_ protein is encoded by a single exon (based on MANE Select transcript NM\_000536.4) and nonsense-mediated decay is not predicted for nonsense or frameshift variants, PVS1 cannot be applied at the default strength to RAG2 variants (indicated by the red boxes in the Flowchart), **except* • in the case of full gene deletion **or* • removing/altering critical domain: the PHD domain and core domain (indicated by the purple in the Flowchart). • PVS1 can be applied to variants not predicted to undergo nonsense-mediated decay when removing/altering the critical PHD domain (spanning amino acids 414-487) and core domain (amino acids 1-383) based on recommendations from Walker et al., preprint. |
| PVS1 - Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, at least one pathogenic variant **must be* • present downstream in order to apply PVS1\_Strong. |
| PVS1 - Moderate | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein, when at least one pathogenic variant is **not* • present downstream, downgrade to PVS1\_Moderate. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as **pathogenic* • by SCID VCEP specifications for _RAG2._ |
| PS1 - Moderate | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as **likely pathogenic* • by SCID VCEP specifications for _RAG2._ |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
| PS2 - Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
Showing 1 to 10 of 107 entries
ClinGen Pulmonary Hypertension Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BMPR2 Version 1.2.0
Rule Set: | |
|---|---|
Disease(s) |
pulmonary arterial hypertension
|
Gene(s) | BMPR2 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. \*\*Use the PVS1 decision tree guide. |
| PVS1 - Strong | Use the PVS1 decision tree guide. |
| PVS1 - Moderate | Use the PVS1 decision tree guide. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established _pathogenic_ variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
| PS1 - Moderate | Same amino acid change as a previously established _likely pathogenic_ variant regardless of nucleotide change. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for IL2RG Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
T-B+ severe combined immunodeficiency due to gamma chain deficiency
|
Gene(s) | IL2RG |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • PVS1 at default strength (Very Strong) can be applied to variants not predicted to undergo nonsense-mediated decay but truncating the transmembrane domain (which begins at amino acid 255) or any distal region (i.e. cytoplasmic domain) due to the lack of functionality of the protein expressed with this defect. |
| PVS1 - Strong | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.874, codon 292, in exon 7), at least one pathogenic variant **must be* • present downstream in order to apply PVS1\_Strong |
| PVS1 - Moderate | Use ClinGen SVI recommendations for loss of function criterion (Tayoun et al., 2018 (PMID: 30192042)) with one specification: • For variants not predicted to undergo nonsense-mediated decay but removing >10% of protein (i.e. variants in the last exon, exon 8, or variants in the last 50 nucleotides of the penultimate exon after c.874, codon 292, in exon 7), when at least one pathogenic variant is **not* • present downstream downgrade to PVS1\_Moderate. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. Applicable if the previously established variant is classified as **pathogenic* • by SCID VCEP specifications for _IL2RG_. |
| PS1 - Moderate | It can also be applied for splice variants at the same nucleotide and with similar impact prediction as previously reported pathogenic variant (if the predicted impact is equal to or greater than the known pathogenic variant per in silico splicing tool SpliceAI). - Example: c.105+1G>C is known to be likely pathogenic, can use PS1 for c.105+1G>T Applicable if the previously established variant is classified as **likely pathogenic* • by SCID VCEP specifications for _IL2RG._ |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
| PS2 - Strong | Use ClinGen SVI recommendations for _de novo_ criteria (see instructions below). |
Showing 1 to 10 of 107 entries
ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACVRL1 Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
telangiectasia, hereditary hemorrhagic, type 2
|
Gene(s) | ACVRL1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ACVRL1 PVS1 Decision Tree (see attachments) |
| PVS1 - Strong | Use ACVRL1 PVS1 Decision Tree (see attachments) |
| PVS1 - Moderate | Use ACVRL1 PVS1 Decision Tree (see attachments) |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Hereditary Hemorrhagic Telangiectasia Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ENG Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
telangiectasia, hereditary hemorrhagic, type 1
|
Gene(s) | ENG |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ENG PVS1 Decision Tree (see attachments) |
| PVS1 - Strong | Use ENG PVS1 Decision Tree (see attachments) |
| PVS1 - Moderate | Use ENG PVS1 Decision Tree (see attachments) |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for HNF1A Version 2.1.0
Rule Set: | |
|---|---|
Disease(s) |
monogenic diabetes
|
Gene(s) | HNF1A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use HNF1A PVS1 decision tree. • Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs. • PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY. • “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” • Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function. • Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118. • Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1. |
| PVS1 - Strong | Use HNF1A PVS1 decision tree. • Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs. • PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY. • “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” • Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function. • Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118. • Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1. |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | Use HNF1A PVS1 decision tree. • Variants generating PTCs 3’ of c.1714 of NM_000545.8, which includes the last 55 nucleotides of exon 9 and all of exon 10, are not expected to cause NMD (PMID: 24274751). The transactivation domain (TAD) of the protein overlaps with this region. The last 55 nucleotides of exon 9 (c.1714-1768) is enriched for disease-causing variants and loss-of function variants in this region have been found in patients/families with a MODY phenotype. Therefore, a “very strong” level of evidence will be used for loss-of-function variants 5’ of c.1768 regardless of where the premature termination codon occurs. • PVS1_Strong will be applied to nonsense variants at c.1803 (p.601) and 5’ and frameshift variants at c.1854 (p.618) and 5’. The distinction of nonsense and frameshift variants was made following a careful review of the phenotypes of individuals with loss-of-function variants in exon 10, which lead to our prediction that the addition of new amino acids from a frameshift will disrupt the TAD and cause a MODY phenotype more so than the deletion of a small part of the end of the TAD. Moderate phenotypic evidence was applied to the c.1802del (p.601Ter) variant, but the individual with the next nonsense variant (p.Gln625Ter) was unaffected. Frameshift variants at p.Ile618 and 5’ have been identified in patients with a phenotype consistent with MODY. • “Exon skipping or use of a cryptic splice site that preserves reading frame” and “Single to multi-exon deletion that preserves reading frame” • Deletions of exon 1 would lead at least to loss of the initiation codon (see below for recommendations for initiation codon variants). Deletions of single exons 2, 3, 4, 5, 6, 8 or 9 all cause frameshift, and thus PVS1 would be used. In HNF1A, only exon 7 (LRG_522t1) is surrounded by introns of the same phase. Skipping or deletion of exon 7 would remove 64 amino acids in the TAD, which is >10% of the protein and 18% of the TAD. Given the significance of the TAD, we support still using PVS1 instead of PVS1_Strong in this situation. A deletion of exon 10 would remove part of the TAD but less than 10% of the protein. Since the TAD is critical to protein function, and variants that disrupt all of exon 10 have been found in patients with a MODY phenotype, we will use PVS1_Strong for deletions of exon 10 and splicing variants that would predict the skipping of exon 10. This specification is in accordance with Tayoun’s recommendation to use PVS1_Strong in cases in which the truncated region is critical to protein function. • Apply PVS1 to initiation codon variants. Four initiation codon variants have been identified in patients with a MODY phenotype. The closest potential in-frame start codon is p.Met118. Starting the protein at p.Met118 would remove 18% of the protein, including the entire dimerization domain. There are many P/LP variants upstream of p.Met118. • Per recommendations from the SVI, when RNA analysis demonstrates abnormal splicing from non-canonical splice site variants, apply PS3 instead of PVS1. |
| PS1 - Very Strong | NA |
| PS1 - Strong | No change |
| PS1 - Moderate | NA |
| PS1 - Supporting | PS1 may also be used at a supporting level for canonical and non-canonical splicing variants when a different variant at the same nucleotide has been previously classified as pathogenic and the variant being assessed is predicted by SpliceAI to have a similar (SpliceAI score within 10% of the original variant) or greater deleterious impact. |
| PS2 - Very Strong | Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications. |
| PS2 - Strong | Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications. |
Showing 1 to 10 of 107 entries
ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
obsolete cerebral malformation
|
Gene(s) | AKT3, MTOR, PIK3CA, PIK3R2 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF). |
| PVS1 - Strong | Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF). |
| PVS1 - Moderate | Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF). |
| PVS1 - Supporting | Not Applicable: LOF and/or haploinsufficiency have not been clearly identified as disease mechanisms underlying brain malformations related to these genes, so in general this rule is not applicable. The disease mechanism for these genes is gain of function (GOF). |
| PS1 - Very Strong | NA |
| PS1 - Strong | No change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity. Criteria 2. The variant is present at a detectable allele fraction in an affected tissue sample but is absent from or detected at a lower allelic fraction in another tissue (e.g. if present in 5% of brain tissue but absent from the blood or skin this point can be awarded). For the sake of implementation, these criteria are intended to apply to high-confidence somatic mutations identified by the reporting CLIA laboratory. The expert panel recognizes that in practice there may be significant heterogeneity in the technical methods and thresholds used to identify such variants as 'high confidence', and flags the need to establish consensus statistical frameworks (e.g. Phred-scaled genotype qualities) or experimental approaches (e.g., confirmation of somatic variants by sequencing on orthogonal platforms) by which quality thresholds can be consistently applied. |
Showing 1 to 10 of 107 entries
ClinGen Glaucoma Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1
Rule Set: | |
|---|---|
Disease(s) |
obsolete glaucoma 1, open angle, E, juvenile open angle glaucoma
|
Gene(s) | MYOC |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay. |
| PVS1 - Strong | Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay. |
| PVS1 - Moderate | Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay. |
| PVS1 - Supporting | Not Applicable: MYOC variants cause JOAG/POAG through a gain of function (GoF) disease mechanism and not loss of function (LoF). Truncating variants in exon 3 are expected to be pathogenic because they escape nonsense-mediated decay. |
| PS1 - Very Strong | NA |
| PS1 - Strong | • The novel change must not affect splicing (SpliceAI ≤ 0.2). |
| PS1 - Moderate | Same amino acid change as a previously established likely pathogenic variant • The novel change must not affect splicing (SpliceAI ≤ 0.2). |
| PS1 - Supporting | NA |
| PS2 - Very Strong | NA |
| PS2 - Strong | ≥2 confirmed de novo in JOAG. Use the proposed SVI point recommendations for “phenotype consistent with gene but not highly specific” for JOAG. • Both maternity and paternity need to be proven for confirmed de novo variants. • Parents need to be clinically assessed and not have a diagnosis of glaucoma. |
Showing 1 to 10 of 107 entries
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.2.0
Rule Set: | |
|---|---|
Disease(s) |
hereditary breast carcinoma, ataxia telangiectasia, ataxia - telangiectasia variant
|
Gene(s) | ATM |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Use ATM PVS1 Decision Tree |
| PVS1 - Strong | Use ATM PVS1 Decision Tree. |
| PVS1 - Moderate | Use ATM PVS1 Decision Tree. |
| PVS1 - Supporting | Use ATM PVS1 Decision Tree |
| PS1 - Very Strong | NA |
| PS1 - Strong | Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. |
| PS1 - Moderate | Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Not Applicable |
| PS2 - Strong | Not Applicable |
Showing 1 to 10 of 107 entries
ClinGen ACADVL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ACADVL Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
very long chain acyl-CoA dehydrogenase deficiency
|
Gene(s) | ACADVL |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Loss of function is a known mechanism for VLCAD Deficiency. The specifications below are based on published guidance for assigning strength of evidence for PVS1 (Abou Tayoun et al., 2018; PMID: 30192042). There are multiple transcripts for ACADVL. The major isoform, NM\_000018.4, encodes a 655 amino acid precursor protein that contains a 40 amino acid N-terminal target sequence that is removed during uptake (Aoyama et al., 1995; PMID: 7668252). In a joint project between NCBI and EMBL-EBI (MANE), NM\_000018.4 was designated as the most relevant transcript. Nonsense or Frameshift: • Use caution when interpreting LOF variants at the 3’ end of the gene. • All nonsense and frameshift variants will meet PVS1 unless the variant is predicted to be missed by nonsense-mediated decay (NMD). • NMD is not predicted if the variant is in the last exon (exon 20) or in the last 50 nucleotides of the penultimate exon (exon 19). Canonical Splice Site (+1, +2, -1, -2): • All donor/acceptor sites follow the GT/AG rule, except for the donor splice site of intron 8, which begins with GC. PVS1 should not be applied for variants in the splice donor site of intron 8 since the impact of GC donor splice sites is not well understood. • For +1 or +2 GT donor splice site variants, the exon immediately 5’ of the variant is predicted to be skipped. For -1 or -2 AG acceptor splice site variants, the exon immediately 3’ of the variants is predicted to be skipped. For the predicted in frame/out of frame consequences for exon skipping in ACADVL (NM\_000018.4), see Appendix 1. Deletions: • For single or multi-exon deletions that result in an out-of-frame consequence, use PVS1 unless NMD is not predicted to occur. If NMD is not predicted to occur, use PVS1\_Moderate. • If a deletion results in an in-frame consequence, the deletion must encompass one or more exons in order to apply PVS1. Consult Appendix 1 and the PVS1 decision tree to assign a strength. Duplications: • Single and multi-exon duplications have not been reported in ACADVL. Consult the PVS1 decision tree to assign the strength. Initiation codon: • The next in-frame methionine is at position 6 (on transcript NM\_000018). However, the first 40 amino acids comprise the leader sequence in the precursor peptide and are important for proper localization of the protein (Aoyama et al., 1995; PMID: 7668252). Therefore, initiator codon variants will meet PVS1\_Strong. • If an in-frame deletion or splice variant disrupts a PM1 region, PVS1 can be modified to Strong instead of Moderate. |
| PVS1 - Strong | NA |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | • Exact same donor/acceptor with a different nucleotide change (PMID: 37352859) |
| PS1 - Moderate | • Exact same donor/acceptor with a different nucleotide change (PMID: 37352859) |
| PS1 - Supporting | • Exact same donor/acceptor with a different nucleotide change (PMID: 37352859) |
| PS2 - Very Strong | Not Applicable |
| PS2 - Strong | Not Applicable |
Showing 1 to 10 of 107 entries
ClinGen FBN1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1
Rule Set: | |
|---|---|
Disease(s) |
Marfan syndrome
|
Gene(s) | FBN1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | • Nonsense/frameshift variants predicted to undergo NMD (not affecting last exon or 55 last nt of penultimate exon). • 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to undergo NMD. • Full gene deletion. • Single to multi-exon deletion disrupting the reading frame and predicted to undergo NMD. • Duplication (>=1 exon in size and completely contained within gene) proven in tandem and disrupting the reading frame and predicted to undergo NMD. |
| PVS1 - Strong | • Nonsense/frameshift variants predicted to escape NMD (affecting last exon, last 55nt of the penultimate exon). • 1,2 splice site variants leading to exon skipping or use of a cryptic splice site disrupting the reading frame and predicted to escape NMD. • 1,2 splice site variants leading to exon skipping or use of a cryptic splice site but preserving the reading frame. • Single to multi-exon deletion disrupting the reading frame and predicted to escape NMD. • Single to multi-exon deletion preserving the reading frame. • Duplication (>=1 exon in size and completely contained within gene) presumed in tandem and presumably disrupting the reading frame and predicted to escape NMD. |
| PVS1 - Moderate | • Initiation codon variant with 1 or more pathogenic variant(s) upstream of closest potential in-frame start codon. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | • Beware of changes that impact splicing rather than the amino acid. Splicing predictions should remain the same for WT and mutant alleles. • Original variant should be pathogenic according to the (modified) ACMG guidelines for variant classification. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Four points |
| PS2 - Strong | Two-three points |
Showing 1 to 10 of 107 entries
ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for OTOF and MYO15A Version 1
Rule Set: | |
|---|---|
Disease(s) |
nonsyndromic genetic hearing loss
|
Gene(s) | MYO15A, OTOF |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications. PVS1 should also be considered for both of the genes OTOF and MYO15A with variants falling in two exons being exceptions to this rule: OTOF: NM_194248.2 Exon 46 (c.5841 to c.5994; PMID: 19250381) and MYO15A: NM_016239.3 Exon 8 (c.4033 to c. 4038; PMID: 10552926) and Exon 26 (c.5911 to c.5964; PMID: 30096381 and high frequency LOF variant https://gnomad.broadinstitute.org/variant/17-18046894-G-A?dataset=gnomad_r2_1) |
| PVS1 - Strong | See PVS1 flow chart for PVS1_Strong variants in gene where LOF is a known mechanism of disease. |
| PVS1 - Moderate | See PVS1 flowchart for PVS1_Moderate variants in gene where LOF is a known mechanism of disease. |
| PVS1 - Supporting | See PVS1 flowchart for PVS1_Supporting variants in gene where LOF is a known mechanism of disease. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant. • Established variant must meet criteria for pathogenicity by the HL specifications. • Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant. • Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T. • No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen. • Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change). |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | 4 points per tables 5a and 5b: Examples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR 4 assumed de novo occurrences. |
| PS2 - Strong | 2 points per tables 5a and 5b: Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences. • OTOF and MYO15A are associated with autosomal recessive conditions. Therefore, de novo variants are expected to be an unlikely occurrence. It is recommended that de novo evidence is only awarded when phase with another variant (VUS, Likely Pathogenic, or Pathogenic) can be confirmed in trans. This is to avoid inappropriately awarding de novo evidence, which would lead to potentially incorrect classification. • Follow recommendations as specified by the Sequence Variant Interpretation working group within ClinGen, as outlined below • Determine number of points per proband using table 1 below. Sum the total number of points for all probands, and determine the strength of the evidence by using table 2. • Please note, the phenotype for de novo occurrences for MYO15A and OTOF are not considered “highly specific”. |
Showing 1 to 10 of 107 entries
ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.3.0
Rule Set: | |
|---|---|
Disease(s) |
DICER1-related tumor predisposition
|
Gene(s) | DICER1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018[1](#pmid_30192042), the following will apply: • Nonsense or frameshift variants: • PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850. • PVS1\_Moderate applies to variants resulting in protein truncation 3’ of this cutoff • Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions: • Exon 10 SDS/SAS: PVS1\_Strong (in-frame but exon includes >10% protein) • Exons 5, 15, 18, 22 SDS/SAS: PVS1\_Moderate (in-frame and each \<10% of protein) • Exon 27 SAS: PVS1\_Moderate (final exon) • Exon 1: no criteria (non-coding) • Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool. |
| PVS1 - Strong | NA |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact. This rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | ≥4 de novo points |
| PS2 - Strong | ≥2 but less than 4 de novo points |
Showing 1 to 10 of 107 entries
ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
AGAT deficiency
|
Gene(s) | GATM |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **Nonsense-mediated decay predicted.** CCDS VCEP notes: Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). GATM specifications: **Nonsense and frameshift variants* • \ • All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\_Strong or PVS1\_Moderate will be applied depending on whether >10% or \<10% of the protein is lost. **Splice site variants (+1, +2, -1, -2)* • \ • All canonical splice site pairs in GATM are GT-AG. \ • For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \ • For the predicted in frame/out of frame consequences of exon skipping and considerations for strength of PVS1, see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \ • If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \ • To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly. \ • Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria. **Deletions (single or multi exon)* • \ • If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\_Strong if >10% of the protein is predicted to be removed, and use PVS1\_Moderate if \<10% of the protein is predicted to be removed. \ • If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\_Strong if more than 10% of the protein is removed and PVS1\_Moderate if \<10% of the protein is removed. \ • If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \ • [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions. **Duplications* • \ • Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications. |
| PVS1 - Strong | **In frame loss of >10% of the protein.* • CCDS VCEP notes: Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). GATM specifications: **Nonsense and frameshift variants* • \ • All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\_Strong or PVS1\_Moderate will be applied depending on whether >10% or \<10% of the protein is lost. **Splice site variants (+1, +2, -1, -2)* • \ • All canonical splice site pairs in GATM are GT-AG. \ • For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \ • For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \ • If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \ • Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria. **Deletions (single or multi exon)* • \ • If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\_Strong if >10% of the protein is predicted to be removed, and use PVS1\_Moderate if \<10% of the protein is predicted to be removed. \ • If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\_Strong if more than 10% of the protein is removed and PVS1\_Moderate if \<10% of the protein is removed. \ • If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \ • [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions. **Duplications* • \ • Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications. |
| PVS1 - Moderate | **Single exon or larger deletion resulting in loss of \<10% of the protein, and initiator codon variants.** CCDS VCEP notes: Loss of function (LOF) of GATM is a known mechanism of disease for arginine:glycine amidinotransferase deficiency (AGAT-D). There are examples of various LOF variants, including nonsense and frameshift, in GATM in individuals with AGAT-D (https://databases.lovd.nl/shared/variants/GATM/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). GATM specifications: **Nonsense and frameshift variants* • \ • All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 9) or the last 50 bases of the penultimate exon (exon 8, 3’ of c.1109). In that case, PVS1\_Moderate will be applied. **Splice site variants (+1, +2, -1, -2)* • \ • All canonical splice site pairs in GATM are GT-AG. \ • For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \*Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \ • For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \ • If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \ • Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria. **Initiator codon variants* • \ • To our knowledge, initiator codon variants have not been reported in GATM (01/2019) but may occur. \ • All initiator codon variants will meet PVS1\_Moderate. The next in-frame methionine is at amino acid position 130 (based on NP\_001473). **Deletions (single or multi exon)* • \ • If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\_Strong if >10% of the protein is predicted to be removed, and use PVS1\_Moderate if \<10% of the protein is predicted to be removed. \ • If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\_Strong if more than 10% of the protein is removed and PVS1\_Moderate if \<10% of the protein is removed. \ • If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \ • [Appendix 1](https://docs.google.com/spreadsheets/d/16DkEaIPdtcYuQ5dqOw9bP3VwEVO4gqJK/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions. **Duplications* • \ • Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | • This criterion is applicable as described. • If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity. CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described. |
| PS2 - Strong | Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity. CCDS VCEP notes for PS2 and PM6: De novo variants have not been reported in patients with AGAT deficiency, to our knowledge. Furthermore, the observation that a variant in GATM has arisen de novo does not support its causality because AGAT deficiency is an autosomal recessive disorder. The occurrence of de novo variants is more supportive in autosomal dominant and X-linked disorders. Any de novo variants in GATM, should they be observed, will be assessed based on the variant type, functional evidence, and in trans data as described. |
Showing 1 to 10 of 107 entries
ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1.1.0
Rule Set: | |
|---|---|
Disease(s) |
guanidinoacetate methyltransferase deficiency
|
Gene(s) | GAMT |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **Nonsense-mediated decay predicted** CCDS VCEP notes: Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). **Nonsense and frameshift variants* • \ • All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\_Strong or PVS1\_Moderate will be applied, depending on whether >10% or \<10% of the protein is lost. **Splice site variants (+1, +2, -1, -2)* • \ • All canonical splice site pairs in GAMT are GT-AG. \ • For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \ • For the predicted in frame/out of frame consequences of exon skipping and assigned strength of PVS1, see [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \ • If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \ • To apply PVS1, splice site variants must have no detectable nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. Otherwise, the PVS1 strength should be reduced accordingly. \ • Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria. **Deletions (single or multi exon)* • \ • If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\_Strong if >10% of the protein is predicted to be removed, and use PVS1\_Moderate if \<10% of the protein is predicted to be removed. \ • If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\_Strong if more than 10% of the protein is removed and PVS1\_Moderate if \<10% of the protein is removed. \ • If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \ • [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions. **Duplications* • \ • Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications. |
| PVS1 - Strong | **In frame loss of >10% of the protein.** CCDS VCEP notes: Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). **Nonsense and frameshift variants* • \ • All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\_Strong will be applied if >10% of the protein is lost. **Splice site variants (+1, +2, -1, -2)* • \ • All canonical splice site pairs in GAMT are GT-AG. \ • For any canonical splice site variant (+1, +2, -1, -2), the exon immediately adjacent to the variant is predicted to be skipped i.e. upstream exon skipped for canonical donor splice site variants and downstream exon skipped for canonical acceptor splice site variants. \ • Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \ • For considerations for strength at which PVS1 may be applied see [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true). \ • If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \ • Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria. **Deletions (single or multi exon)* • \ • If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\_Strong if >10% of the protein is predicted to be removed, and use PVS1\_Moderate if \<10% of the protein is predicted to be removed. \ • If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\_Strong if more than 10% of the protein is removed and PVS1\_Moderate if \<10% of the protein is removed. \ • If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \ • [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions. **Duplications* • \ • Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications. |
| PVS1 - Moderate | **Single exon or larger deletion resulting in loss of \<10% of the protein.** **Initiator codon variant.* • CCDS VCEP notes: Loss of function (LOF) of GAMT is a known mechanism of disease for guanidinoacetate methyltransferase deficiency (GAMT-D). There are examples of various LOF variants, including nonsense and frameshift, in GAMT in individuals with GAMT-D (https://databases.lovd.nl/shared/variants/GAMT/unique). The specifications below are based on the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042). **Nonsense and frameshift variants* • \ • All nonsense and frameshift variants will meet PVS1 unless a premature termination codon is predicted to be missed by nonsense-mediated decay (NMD) because it is located in the last exon (exon 6) or the last 50 bases of the penultimate exon of the gene (exon 5, c.520). In that case, PVS1\_Moderate will be applied if \<10% of the protein is lost. **Splice site variants (+1, +2, -1, -2)* • \ • All canonical splice site pairs in GAMT are GT-AG. \ • Use SpliceAI and varSEAK to look for nearby (+/- 20 nucleotides) strong consensus splice sequence that may reconstitute in-frame splicing. \ • For any canonical splice site variant (+1, +2, -1, -2), if RT-PCR data predicts in-frame loss of \<10% of the protein, apply PVS1\_Moderate. \ • If this criterion is applied, PP3 (in silico splice site prediction tools) should not be used. \ • Non-canonical splice variants, such as +3 or -3, will not meet PVS1, but could meet PS3 and/or PP3 criteria. **Initiator codon variants* • \ • To our knowledge, initiator codon variants have not been reported in GAMT (01/2019) but may occur. \ • All initiator codon variants will meet PVS1\_Moderate. The next in-frame methionine is at amino acid position 42 (based on NP\_000147.1). **Deletions (single or multi exon)* • \ • If a single or multi-exon deletion results in an out of frame consequence, use PVS1 unless not predicted to undergo NMD. If not predicted to undergo NMD, use PVS1\_Strong if >10% of the protein is predicted to be removed, and use PVS1\_Moderate if \<10% of the protein is predicted to be removed. \ • If the consequence is in frame, the deletion must encompass one or more exons for PVS1 to apply. Use PVS1\_Strong if more than 10% of the protein is removed and PVS1\_Moderate if \<10% of the protein is removed. \ • If the in frame deletion is smaller than one exon, PVS1 does not apply; consider using PM4. \ • [Appendix 1](https://docs.google.com/spreadsheets/d/14TbVpD0EkHQF6AqGfUqc9oaaF-LN8Zjn/edit?usp=sharing&ouid=116554599135667874749&rtpof=true&sd=true) can be used to predict the consequences of single exon deletions. **Duplications* • \ • Use the PVS1 decision tree (Figure 1, Abou Tayoun et al, 2018, PMID 30192042) to assess the impact of duplications. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | This criterion is applicable as described. If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity. |
| PS2 - Strong | Not Applicable: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC6A8 Version 1.2.0
Rule Set: | |
|---|---|
Disease(s) |
creatine transporter deficiency
|
Gene(s) | SLC6A8 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | • Loss of function is a known mechanism of disease for Creatine Transporter Deficiency. • Specifications are based on the decision tree as outlined in Tayoun etal, 2018 (Hum Mutat. 2018 Nov;39(11):1517-1524; PMID: 30192042) SLC6A8: PVS1, at appropriate strength, is applicable as described in Abou Tayoun et al, 2018 (PMID: 30192042) |
| PVS1 - Strong | NA |
| PVS1 - Moderate | NA |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | • This criterion is applicable as for any variant resulting in the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. • If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing. • PS1 may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859). |
| PS1 - Moderate | • This criterion is applicable as for any variant resulting in the same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. • If the variant is in the last 3 nucleotides of an exon, further analysis using splicing site prediction algorithms (see PP3) and data from the literature (if available) is required to investigate the impact on splicing. • PS1\_Moderate may also be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859). |
| PS1 - Supporting | PS1\_Supporting may be applied for splicing variants under specific circumstances (see Table 3 in PMID: 37352859). |
| PS2 - Very Strong | NA |
| PS2 - Strong | Note: Confirmation of paternity in females only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. X-linked disorder. Only maternity needs to be confirmed. |
Showing 1 to 10 of 107 entries
ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 3.0.0
Rule Set: | |
|---|---|
Disease(s) |
Pitt-Hopkins syndrome
|
Gene(s) | TCF4 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group (PMID:30192042). • PVS1 is applicable up to p.E643 which corresponds to the distal most de novo truncating variant in an affected patient reported to date.[1](#PMID_29695756) • PVS1 can be applied for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-of-frame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 15). |
| PVS1 - Strong | NA |
| PVS1 - Moderate | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Moderate is applicable for any truncating variant distal of p.E643 and for single exon deletions that involve just non-coding exon 20. |
| PVS1 - Supporting | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Supporting is applicable for initiation codon variants in _TCF4._ |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • ≥2 independent occurrences of PS2. • ≥2 independent occurrences of PM6 and one occurrence of PS2. • Evidence from literature must be fully evaluated to support independent events. |
| PS2 - Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. |
Showing 1 to 10 of 107 entries
ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SLC9A6 Version 3.0.0
Rule Set: | |
|---|---|
Disease(s) |
Christianson syndrome
|
Gene(s) | SLC9A6 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group (PMID:30192042). • PVS1 is applicable up to p.A563, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single exon in-frame deletion predicted to preserve the reading frame (exon 10), and multiple in-frame exon deletions that include exon 10. |
| PVS1 - Strong | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Strong is applicable for any truncating variant from p.C564 to p.T601 and for canonical splice site variants that flank exon 3 (in-frame exon).[2](#PMID_27256868),[3](#PMID_19377476),[1](#PMID_18342287) |
| PVS1 - Moderate | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Moderate is applicable for any truncating variant between p.Y602 to p.A669 and any frameshift variant that results in a read-through of the stop codon. |
| PVS1 - Supporting | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Supporting is applicable for initiation codon variants in _SLC9A6_ |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • ≥2 independent occurrences of PS2. • ≥2 independent occurrences of PM6 and one occurrence of PS2. • Evidence from literature must be fully evaluated to support independent events. |
| PS2 - Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • 1 occurrence of PS2 |
Showing 1 to 10 of 107 entries
ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 3.0.0
Rule Set: | |
|---|---|
Disease(s) |
CDKL5 disorder
|
Gene(s) | CDKL5 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group (PMID:30192042). • PVS1 is applicable up to p.R948 **when using the major brain isoform which has an alternative C-terminus (NM\_001323289.2)**, for canonical splice site variants predicted to result in an out-of-frame product, for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exons 7, 10, 13), and for the non-coding CDKL5 exon (exon 1). |
| PVS1 - Strong | NA |
| PVS1 - Moderate | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Moderate is applicable for any truncating variant distal of p.R948.(**when using the major brain isoform, NM\_001323289.2**) and for canonical splice site variants that flank exon 17 (in-frame exon). |
| PVS1 - Supporting | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Supporting is applicable for initiation codon variants in _CDKL5._ |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • ≥2 independent occurrences of PS2. • ≥2 independent occurrences of PM6 and one occurrence of PS2. |
| PS2 - Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history.\\ • 1 occurrence of PS2. |
Showing 1 to 10 of 107 entries
ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXG1 Version 3.0.0
Rule Set: | |
|---|---|
Disease(s) |
FOXG1 disorder
|
Gene(s) | FOXG1 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group (PMID:30192042). • PVS1 is applicable up to p.S468[1](#PMID_30525188) |
| PVS1 - Strong | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Strong is applicable for any truncating variant from p.G469 to p.Q480[6](#PMID_29655203). |
| PVS1 - Moderate | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Moderate is applicable for any truncating variant distal of p.Q480. |
| PVS1 - Supporting | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Supporting is applicable for initiation codon variants in _FOXG1._ |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • ≥2 independent occurrences of PS2. • ≥2 independent occurrences of PM6 and one occurrence of PS2. • Evidence from literature must be fully evaluated to support independent events. |
| PS2 - Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • 1 occurrence of PS2. |
Showing 1 to 10 of 107 entries
ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MECP2 Version 3.0.0
Rule Set: | |
|---|---|
Disease(s) |
Rett syndrome
|
Gene(s) | MECP2 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group (PMID:30192042). • PVS1 is applicable up to p.E472, for any frameshift variant that results in a read-through of the stop codon, for canonical splice site variants predicted to result in an out-offrame product, and for canonical splice site variants or single in-frame deletions predicted to preserve the reading frame (exon 3). PVS1 is not applicable for initiation codons |
| PVS1 - Strong | NA |
| PVS1 - Moderate | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1\_Moderate is applicable for any truncating variant distal of p.E472. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • ≥2 independent occurrences of PS2. • ≥2 independent occurrences of PM6 and one occurrence of PS2. |
| PS2 - Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • 1 occurrence of PS2. |
Showing 1 to 10 of 107 entries
ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for UBE3A Version 4.0.0
Rule Set: | |
|---|---|
Disease(s) |
Angelman syndrome
|
Gene(s) | UBE3A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Null variant in a gene where loss of function is a known mechanism of disease. • Use as defined by ClinGen SVI working group (PMID:30192042). • PVS1 is applicable for any truncating variant up to p.K841[5](#PMID_9887341), for any frameshift variant that results in a read-through of the stop codon, for initiation codon variants, for canonical splice site variants predicted to result in an out-of-frame product, and for intragenic deletions/duplications predicted to result in an out-of-frame product. |
| PVS1 - Strong | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1_Strong is applicable for any truncating variant from p.K842 to p.G850 and for canonical splice site variants that flank exons 7, 8 (in-frame exons). |
| PVS1 - Moderate | Null variant in a gene where loss of function is a known mechanism of disease. • PVS1_Moderate is applicable for any truncating variant distal of p.G850. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. |
| PS1 - Moderate | NA |
| PS1 - Supporting | NA |
| PS2 - Very Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • ≥2 independent occurrences of PS2. • ≥2 independent occurrences of PM6 and one occurrence of PS2. • Evidence from literature must be fully evaluated to support independent events. |
| PS2 - Strong | De novo (maternity and paternity confirmed) in a patient with the disease and no family history. • 1 occurrence of PS2. |
Showing 1 to 10 of 107 entries
ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1A Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
Dravet syndrome, generalized epilepsy with febrile seizures plus, developmental and epileptic encephalopathy
|
Gene(s) | SCN1A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Moderate | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Supporting | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1601. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Pathogenic* • variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. • **\>1* • Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Moderate | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Likely Pathogenic* • variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Supporting | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS2 - Very Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points* • will arrive at **Very Strong**. Dravet\*: 2 points Genetic Epilepsy with Febrile Seizures Plus: 1 point Developmental and Epileptic Encephalopathy: 1 point Hemiplegic migraine: 0.5 points Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points* • will arrive at **Strong**. Dravet\*: 2 points Genetic Epilepsy with Febrile Seizures Plus: 1 point Developmental and Epileptic Encephalopathy: 1 point Hemiplegic migraine: 0.5 points Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN2A Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
complex neurodevelopmental disorder
|
Gene(s) | SCN2A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Moderate | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Supporting | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN2A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1591. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. • **\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Moderate | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Supporting | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS2 - Very Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points* • will arrive at **Very Strong**. • Complex Neurodevelopmental Disorder: 1 points • Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points* • will arrive at **Strong**. • Complex Neurodevelopmental Disorder: 1 points • Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN3A Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
developmental and epileptic encephalopathy
|
Gene(s) | SCN3A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Moderate | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Supporting | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN3A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1586. In-frame exons: 1, 7, 8, 12, 17, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. • **\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Moderate | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Supporting | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS2 - Very Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points* • will arrive at **Very Strong**. Developmental and Epileptic Encephalopathy: 1 point Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points* • will arrive at **Strong**. Developmental and Epileptic Encephalopathy: 1 point Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN8A Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
complex neurodevelopmental disorder
|
Gene(s) | SCN8A |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Moderate | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Supporting | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN8A-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr1582. In-frame exons: 1, 7, 8, 12, 17, 19, 25 Out-of-frame exons: 2-6, 9-11, 13-16, 18, 20-24, 26 Truncated/altered protein is critical to protein funtion if the region falls within a Pathogenic Enriched Region, as defined in “PM1 Table”. For splice region variants, this criterion should not be applied with PP3. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. • **\>1** Identical amino acid change in paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). See Paralogous Gene Table for corresponding amino acid positions. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Moderate | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • Same amino acid change as a previously established **Likely Pathogenic** variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Supporting | Same/identical amino acid change as previously reported (Caveat: beware of changes that impact splicing rather than at the amino acid/protein level). • A single identical amino acid change in a paralogous gene previously established as **Pathogenic or Likely Pathogenic**, including NDD genes with equivalent constraint scores (SCN1A, SCN2A, SCN3A, SCN8A). Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS2 - Very Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points* • will arrive at **Very Strong**. • Complex Neurodevelopmental Disorder: 1 points • Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points* • will arrive at **Strong**. • Complex Neurodevelopmental Disorder: 1 points • Other phenotypes not consistent w/neurodevelopmental disorder: 0 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
hemophilia A
|
Gene(s) | F8 |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree. |
| PVS1 - Strong | Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree. |
| PVS1 - Moderate | Per Coagulation Factor Deficiency VCEP/SVI PVS1 decision tree. |
| PVS1 - Supporting | NA |
| PS1 - Very Strong | NA |
| PS1 - Strong | This evidence code can be applied when there is 1 pathogenic variant or 2 likely pathogenic variants at the same residue based on _F8_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggest a splicing defect. |
| PS1 - Moderate | This evidence code can be applied when there is 1 likely pathogenic variants at the same residue based on _F8_ gene rule specifications from the Coagulation Factor Deficiency VCEP and where _in silico_ predictors do not suggesting a splicing defect. |
| PS1 - Supporting | NA |
| PS2 - Very Strong | Use the SVI recommendations for de novo cases; 4 points. Use de novo guidance below to determine point value. |
| PS2 - Strong | Use the SVI recommendations for de novo cases; 2 points. Use de novo guidance below to determine point value. |
Showing 1 to 10 of 107 entries
ClinGen Epilepsy Sodium Channel Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SCN1B Version 1.0.0
Rule Set: | |
|---|---|
Disease(s) |
generalized epilepsy with febrile seizures plus, developmental and epileptic encephalopathy
|
Gene(s) | SCN1B |
Genetype | nuclear |
Criteria Code | Strength Specification |
| PVS1 - Very Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. In-frame exons: 3-5 Out-of-frame exons: 1-2 For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Strong | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. In-frame exons: 3-5 Out-of-frame exons: 1-2 For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Moderate | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. In-frame exons: 3-5 Out-of-frame exons: 1-2 For splice region variants, this criterion should not be applied with PP3. |
| PVS1 - Supporting | **Follow SVI guidance per workflow in Tayoun et al (2018), included as “PVS1 Decision Tree”, using SCN1B-specific information.** Most terminal codon predicted to undergo nonsense-mediated decay (NMD) p.Thr204. In-frame exons: 3-5 Out-of-frame exons: 1-2 For splice region variants, this criterion should not be applied with PP3. |
| PS1 - Very Strong | NA |
| PS1 - Strong | Same amino acid change as a previously established **Pathogenic* • variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Moderate | Same amino acid change as a previously established **Likely Pathogenic* • variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS1 - Supporting | Same predicted impact on splicing as previously classified variant (Refer to Table 2 in Walker et al, 2023). • PS1 can be applied at varying strengths for splice variants, in conjunction with either PP3 or PVS1. PS1 strength depends on location of the variant under assessment (within or outside the +/- 1,2 dinucleotide positions) and the location of the previously classified variant (within or outside the +/- 1,2 dinucleotide position). Specific combinations are outlined in Table 2 in Walker, et al (2023) PMID: 37352859, also provided as a supplement ("PS1\_Variants impacting splicing"). |
| PS2 - Very Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **4 points* • will arrive at **Very Strong**. Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
| PS2 - Strong | De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Points based system for each unrelated proband determined by phenotypic specificity. Total of **2 points* • will arrive at **Strong**. Genetic Epilepsy with Febrile Seizures Plus (GEFS+): 1 point Other epilepsy types or syndromes not included above, with or without associated neurodevelopmental features: 0.5 points Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. |
Showing 1 to 10 of 107 entries
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