{ "data": [ { "entContent": { "label": "PS2", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0241", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 8, "id": "0016", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 4, "id": "0051", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Award the PS2_Strong point if Criteria 1 AND Criteria 2 are fulfilled. \n\n Criteria 1. The variant is present at a detectable allele fraction but is absent from parental samples with confirmed maternity and paternity.\n\n 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).\n\nFor 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.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 2, "id": "004", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Award the PS2_Moderate point if Criteria 1 is fulfilled, OR if parents are not available but Criteria 2 is fulfilled.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 1, "id": "0043", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478040" }, { "entContent": { "label": "BP4", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0215", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0213", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -4, "id": "0066", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -2, "id": "0214", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": -1, "id": "0080", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Award BP4 for a synonymous, intronic positions (except canonical splice sites) or non-coding variants in the UTRs, if two out of three of the splicing prediction tools predicted no impact on splicing function.\nNot applicable for any variant type except for synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs,. This criterion can be applied when two of three splicing prediction tools predict no splicing change. The splicing prediction tools used are: varSEAK, spliceAI and MaxEntScan.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478041" }, { "entContent": { "label": "PP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0236", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0042", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 4, "id": "0023", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 2, "id": "0040", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 1, "id": "0060", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478042" }, { "entContent": { "label": "PP4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0239", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "002", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "005", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0018", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0063", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478043" }, { "entContent": { "label": "PM2", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0231", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0044", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0013", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 2, "id": "0011", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 1, "id": "0030", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Absent/rare from controls in an ethnically-matched cohort population sample ( ≥1).", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478044" }, { "entContent": { "label": "PP3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0238", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0024", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0019", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0025", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0062", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478045" }, { "entContent": { "label": "PP2", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0237", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0049", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0033", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0034", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 1, "id": "0061", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Missense constraint computed in ExAC/gnomAD was utilized. Award PP2 if the z-score > 3.09. (applicable to MTOR, PIK3CA and AKT3 but not PIK3R2).", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478046" }, { "entContent": { "label": "BA1", "strengthDescriptor": [ { "applicability": "Applicable", "defaultPoint": "Not Applicable", "id": "0087", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "Allele frequency (>0.0926%). An allele frequency (>0.0926%) was approved.\n Note: this was adjusted from ACMG Guidelines due to maintaining the 5x threshold for benign (consistent with previously established guidelines)", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0201", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0202", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0203", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0089", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478047" }, { "entContent": { "label": "PM4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0233", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0012", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 4, "id": "0035", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 2, "id": "009", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 1, "id": "0059", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478048" }, { "entContent": { "label": "BS2", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0091", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000357", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0224", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": -4, "id": "0069", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Award BS2 if ≥3 homozygotes present in gnomAD or ≥3 heterozygous in well phenotyped family members.\nClinical laboratories are encouraged to accumulate more than 2 (≥3) instances of well phenotyped family members before applying this strong criterion. To be considered for this point, the variant should be either germline (most common), or somatic in a relevant tissue. Homozygous occurrences in gnomAD or ExAC can also be counted for this point (≥3).", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -2, "id": "0098", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -1, "id": "0076", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478049" }, { "entContent": { "label": "BS1", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0090", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0222", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": -4, "id": "0070", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Allele frequency (>0.0185%). An allele frequency (>0.0185%) was approved. (Supplemental Table 3).", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -2, "id": "0223", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -1, "id": "0086", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478050" }, { "entContent": { "label": "PS1", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0240", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0021", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 4, "id": "0050", "instructionsToUse": "", "specificationType": [ "None" ], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "No change.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 2, "id": "0046", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 1, "id": "0036", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478051" }, { "entContent": { "label": "PM1", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0230", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0015", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 4, "id": "0028", "instructionsToUse": "", "specificationType": "Disease-specific", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 2, "id": "006", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 1, "id": "0054", "instructionsToUse": "", "specificationType": [ "Strength" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Residues affecting critical functional domains provided in Table 4 for each gene.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478052" }, { "entContent": { "label": "BP6", "strengthDescriptor": [ { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Very Strong", "strengthSepioID": "", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Moderate", "strengthSepioID": "SEPIO:0000326", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478053" }, { "entContent": { "label": "BP7", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0221", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0219", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -4, "id": "0065", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -2, "id": "0220", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": -1, "id": "0079", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "For synonymous, intronic positions (except canonical splice sites) and non-coding variants in the UTRs, if the nucleotide is non-conserved award this point (PhyloP score <0.1).", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478054" }, { "entContent": { "label": "BS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0229", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0227", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0071", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0228", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0077", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478055" }, { "entContent": { "label": "BS3", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0226", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0225", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0072", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0100", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0001327", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0085", "instructionsToUse": "", "specificationType": [ "Strength" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the Brain Malformation Group for quality metrics and minimum validation controls required.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478056" }, { "entContent": { "label": "PS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0243", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 8, "id": "0029", "instructionsToUse": "", "specificationType": "Disease-specific, Strength", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 4, "id": "0053", "instructionsToUse": "", "specificationType": "Disease-specific", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 2, "id": "0057", "instructionsToUse": "", "specificationType": "Strength", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 1, "id": "0032", "instructionsToUse": "", "specificationType": "Strength", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478057" }, { "entContent": { "label": "PM5", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0234", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0047", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 4, "id": "0056", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 2, "id": "008", "instructionsToUse": "", "specificationType": [ "None" ], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "No change.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 1, "id": "0048", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": 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"EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": -1, "id": "0081", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478059" }, { "entContent": { "label": "BP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0206", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0204", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0075", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0205", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0082", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478060" }, { "entContent": { "label": "BP2", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0209", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0207", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0068", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0208", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0084", "instructionsToUse": "", "specificationType": [ "None" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Observed in cis or trans with a known pathogenic variant in the same gene.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478061" }, { "entContent": { "label": "PVS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0245", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 8, "id": "0017", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 4, "id": "0020", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 2, "id": "0026", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "defaultPoint": 1, "id": "001", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478062" }, { "entContent": { "label": "BP5", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0218", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0216", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -4, "id": "0073", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": -2, "id": "0217", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": -1, "id": "0078", "instructionsToUse": "", "specificationType": [ "None" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "No change.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478063" }, { "entContent": { "label": "PS3", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0242", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "defaultPoint": 8, "id": "0031", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 4, "id": "0052", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required. (Supplemental Document 1) Animal models are considered in a different manner.\n\nAward PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors shows a complementary brain phenotype.\n\nAward PS3 if the functional assay meets the acceptability criteria delimited in (PMID: 31892348) with specifications added by the BMVCEP. Quality metrics and minimum validation controls required can be found in Supplementary Document 1.\n\nAnimal models are considered in a different manner. Award PS4_Strong if the animal model generated with the variant of interest expressed in neural progenitors show a complementary brain phenotype.\n\nCaveat: Studies of cell lines derived from the affected patient as the only source of functional characterization are by themselves insufficient to provide strong evidence of pathogenicity. This is because cells derived from patient affected tissue are likely to exhibit the desired phenotype since the patient tissue exhibits the phenotype. It is therefore impossible to determine whether the variant of interest was solely responsible for that phenotype. Instead, functional readout of patient-derived cells are now included in PS4.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 2, "id": "0039", "instructionsToUse": "", "specificationType": [ "Strength" ], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348). Animal models are considered in a different manner. Award PS4_Moderate if the animal model generated with the variant of interest expressed in non-neural tissues show an increased cancer burden.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "defaultPoint": 1, "id": "0045", "instructionsToUse": "", "specificationType": [ "Strength" ], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Follow recommendations set forth by the SVI in conjunction with specifications added by the BMVCEP for quality metrics and minimum validation controls required (PMID: 31892348).", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478064" }, { "entContent": { "label": "PM6", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0235", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0014", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0037", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0010", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0022", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478065" }, { "entContent": { "label": "PM3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0232", "instructionsToUse": "", "specificationType": [], "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0038", "instructionsToUse": "", "specificationType": [], "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0058", "instructionsToUse": "", "specificationType": [], "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "007", "instructionsToUse": "", "specificationType": [], "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0027", "instructionsToUse": "", "specificationType": [], "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478066" }, { "entContent": { "label": "PP5", "strengthDescriptor": [ { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Stand Alone", "strengthSepioID": "", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1113478067" }, { "entContent": { "label": "BP4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0215", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0213", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0066", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0214", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Caveats": [ "Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant." ] }, "applicability": "Applicable", "id": "0080", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "* For missense variants: REVEL score ≤0.15 and SpliceAI score ≤0.1.\n* For synonymous and intronic variants: SpliceAI score ≤0.1.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552545" }, { "entContent": { "label": "PP3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0238", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0024", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0019", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0025", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Caveats": [ "Because many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant." ] }, "applicability": "Applicable", "id": "0062", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "* For missense variants: REVEL score ≥0.644 or SpliceAI score ≥0.2.\n* For synonymous and intronic variants: SpliceAI score ≥0.2.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552546" }, { "entContent": { "label": "BS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0226", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0225", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0072", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0100", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0001327", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0085", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "* mRNA splicing assays \n* Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling\n* Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)\n* Subcellular protein localization\n* Morphology: Morphology & actin cytoskeleton, tubulogenesis", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552547" }, { "entContent": { "label": "BP5", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0218", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0216", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0073", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0217", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0078", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Apply if a likely pathogenic or pathogenic variant (based on HHT VCEP rules) is found in _ENG_.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552548" }, { "entContent": { "label": "PS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0242", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0031", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Notes": [ "Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well established." ] }, "applicability": "Applicable", "id": "0052", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "* mRNA splicing assays can be used as strong functional evidence. \n * **Note:** level of evidence used may differ depending on whether the abnormal transcript is in-frame or out-of-frame, and whether there is complete or incomplete splicing impact.\n * Do not use PS3 for splice variants that meet PVS1.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0039", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "See PS3\\_Supporting and Instructions below.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0045", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "* Protein expression assays: Metabolic label & IP, WB & FACS HUVECs/BOECs, FACs activated monocytes, cDNA transfect, WB & ML HEK293T/COS/NIH3T3, cDNA transfect & luciferase HepG2\n * **Note:** Decreased protein expression can be used as supporting pathogenic evidence if experiment was not done in a single assay, and the corresponding densitometry of western blot reflects the conclusion drawn.\n* Intracellular signaling assays: BRE/CAGA-luciferase, Gal4 Smad1/Smad3 for TGF-beta/BMP9 signaling\n* Binding assays: BMP9 binding, transcription factor Sp1, BMP9 protein-protein interaction (BLI)\n* Subcellular protein localization\n* Morphology: Morphology & actin cytoskeleton, tubulogenesis\n* Somatic variant 2nd hit: In vivo evidence can be obtained as supporting functional evidence by identification of somatic variants in telangiectases´ biopsies using NGS, suggesting a second-hit mechanism leading to biallelic LOF (PMID: 31630786).", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552550" }, { "entContent": { "label": "PM3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0232", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0038", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0058", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Notes": [ "This requires testing of parents (or offspring) to determine phase." ] }, "applicability": "Not applicable", "id": "007", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0027", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552551" }, { "entContent": { "label": "BA1", "strengthDescriptor": [ { "applicability": "Applicable", "id": "0087", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "Allele frequency is ≥1% in general population databases (e.g. gnomAD) based on Popmax FAF.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0201", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0202", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0203", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0089", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552552" }, { "entContent": { "label": "PM2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0231", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0044", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0013", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Caveats": [ "Population data for insertions/deletions may be poorly called by next-generation sequencing." ] }, "applicability": "Not Applicable", "id": "0011", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0030", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "\\<6 total alleles in gnomAD or \\<0.00004 (0.004%) in gnomAD subpopulations.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552553" }, { "entContent": { "label": "BP7", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0221", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0219", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0065", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0220", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0079", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "A synonymous or intronic variant for which SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site. Can be used together with BP4 evidence.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552554" }, { "entContent": { "label": "PVS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0245", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Caveats": [ "Beware of genes where LOF is not a known disease mechanism (e.g., GFAP, MYH7)", "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 caution in the presence of multiple transcripts" ] }, "applicability": "Applicable", "id": "0017", "instructionsToUse": "", "specificationType": [ "Gene-specific", "Strength" ], "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "Use ACVRL1 PVS1 Decision Tree (see attachments)", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0020", "instructionsToUse": "", "specificationType": [ "Gene-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Use ACVRL1 PVS1 Decision Tree (see attachments)", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0026", "instructionsToUse": "", "specificationType": [ "Gene-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Use ACVRL1 PVS1 Decision Tree (see attachments)", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "001", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552555" }, { "entContent": { "label": "PS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0243", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0029", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Notes": [ "Relative risk or OR, as obtained from case–control studies, is >5.0, and the confidence interval around the estimate of relative risk or OR does not include 1.0. See the article for detailed guidance.", "In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence." ] }, "applicability": "Applicable", "id": "0053", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "4+ probands with phenotype consistent with HHT.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0057", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": " 2-3 probands with phenotype consistent with HHT.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0032", "instructionsToUse": "", "specificationType": [ 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"strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant 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Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation." ] }, "applicability": "Applicable", "id": "0071", "instructionsToUse": "", "specificationType": [ "Clarification", "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Lack of segregation in affected members of a family.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0228", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0077", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552560" }, { "entContent": { "label": "PP2", "strengthDescriptor": [ { "applicability": "Not 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"ldhId": "1161552561" }, { "entContent": { "label": "BS2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0091", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000357", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0224", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0069", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0098", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0076", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552562" }, { "entContent": { "label": "PM4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0233", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0012", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0035", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "009", "instructionsToUse": "", "specificationType": [ "None" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0059", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552563" }, { "entContent": { "label": "BP6", "strengthDescriptor": [ { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Very Strong", "strengthSepioID": "", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "instructionsToUse": "", "strength": "Moderate", "strengthSepioID": "SEPIO:0000326", "text": "This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552564" }, { "entContent": { "label": "PS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0240", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0021", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Caveats": [ "Beware of changes that impact splicing rather than at the amino acid/protein level" ], "Example": [ "Val=>Leu caused by either G>C or G>T in the same codon" ] }, "applicability": "Applicable", "id": "0050", "instructionsToUse": "", "specificationType": [ "No change" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\nExample: Val->Leu caused by either G>C or G>T in the same codon.\nCaveat: Beware of changes that impact splicing rather than at the amino acid/protein level.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0046", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0036", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552565" }, { "entContent": { "label": "PP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0236", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0042", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0023", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "5+ meioses (1/32 likelihood)", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0040", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "4 meioses (1/16 likelihood)", "type": "EvidenceLineStrength" }, { "additionalComments": { "Notes": [ "May be used as stronger evidence with increasing segregation data" ] }, "applicability": "Applicable", "id": "0060", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "3 meioses (1/8 likelihood)", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552566" }, { "entContent": { "label": "PM1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0230", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0015", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0028", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "006", "instructionsToUse": "", "specificationType": [ "Gene-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Apply if variant is located in a critical residue:\n\n* _ACVRL1_:\n * glycine-rich loop: G209-V216\n * phosphate anchor: K229\n * C-helix E pairing the phosphate anchor: E242\n * catalytic loop: R329-N335\n * metal-binding loop: D348-L351\n * _BMP10_ interaction cluster\n * (His40, Val54, Val56, Arg57, Glu58, Glu59, His66, Asn71, Leu72, His73, Glu75, Leu76, Arg78, Gly79, Arg80, Thr82, Glu83, Phe84, Val85, His87)", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0054", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552567" }, { "entContent": { "label": "BP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0206", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0204", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0075", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0205", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0082", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552568" }, { "entContent": { "label": "PM5", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0234", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0047", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0056", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "≥2 different missense changes at same codon have been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.", "type": "EvidenceLineStrength" }, { "additionalComments": { "Examples": [ "Arg156His is pathogenic; now you observe Arg156Cys" ] }, "applicability": "Applicable", "id": "008", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "A different missense change at same codon has been determined to be likely pathogenic or pathogenic based on HHT VCEP rules.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0048", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552569" }, { "entContent": { "label": "BS1", "strengthDescriptor": [ { "applicability": "Not Applicable", "id": "0090", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0222", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0070", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "\\>0.2% to \\<1% in general population databases (e.g. gnomAD) based on Popmax FAF, **or** if variant meets BS1\\_Supporting and has ≥2 homozygotes.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0223", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0086", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": " >0.08% to 0.2% (based on gnomAD Popmax FAF).", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552570" }, { "entContent": { "label": "PS2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0241", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0016", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "additionalComments": { "Notes": [ "Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, and so on, can contribute to nonmaternity." ] }, "applicability": "Applicable", "id": "0051", "instructionsToUse": "", "specificationType": [ "Clarification", "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.\nNote: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "004", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0043", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552571" }, { "entContent": { "label": "BP2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0209", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0207", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0068", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable", "id": "0208", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable", "id": "0084", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Observed in trans with a pathogenic or likely pathogenic variant based on HHT VCEP rules.", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552572" }, { "entContent": { "label": "BP3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0212", "instructionsToUse": "", "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0210", "instructionsToUse": "", "status": "approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0074", "instructionsToUse": "", "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0211", "instructionsToUse": "", "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0081", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "1161552574" }, { "entContent": { "label": "BS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0090", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0222", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0070", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Variant has a PopMax FAF ≥0.002 (0.2%) in gnomAD.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0223", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0086", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637691" }, { "entContent": { "label": "PM3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0232", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0038", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0058", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "007", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "This criterion can be used for a candidate LDLR variant observed in an individual with a homozygous FH phenotype when there is only one other pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9. Caveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0027", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637692" }, { "entContent": { "label": "BS2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0091", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000357", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0224", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0069", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Variant is identified in ≥3 heterozygous or ≥1 homozygous well-phenotyped, untreated, normolipidemic adults (unrelated).", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0098", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0076", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637693" }, { "entContent": { "label": "PM4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0233", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0012", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0035", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "009", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "In-frame deletion/insertions smaller than one whole exon, or in-frame whole-exon duplications not considered in any PVS1 criteria.\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0059", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637694" }, { "entContent": { "label": "BS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0226", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0225", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0072", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Variant meets Level 1 benign functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with no endogenous LDLR) transfected with mutant plasmid. Assay result of >90% of wild-type activity in expression/biosynthesis, binding AND internalization.\nNote: studies of only part of the LDLR cycle are not eligible for BS3 or BS3_Supporting. ", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0100", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0001327", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0085", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Variant meets Level 3 benign functional study criteria. See Table 3.\n(1) Study of whole LDLR cycle in a) true homozygous patient cells, with assay result of >90% of wild-type activity in biosynthesis, binding AND internalization; or in b) heterozygous patient cells with assay result of >95% of wild-type activity in biosynthesis, binding AND internalization.\n(2) Luciferase studies with transcription levels of >90% when compared to wild-type (applicable to 5’UTR/promoter variants).\n(3) RNA studies, using RNA extracted from heterozygous or homozygous patientcells, with a) aberrant transcripts quantification, where aberrant transcript is<10% of total transcript OR b) without transcript quantification where noaberrant transcript is confirmed by sequencing.\n(4) Minigene splicing assay where only wild-type transcript is present and confirmed by sequencing.\n(5) High-throughput assays as defined above; only applicable when assay canindicate the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding AND internalization) is unaffected.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637695" }, { "entContent": { "label": "PM5", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0234", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0047", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0056", "instructionsToUse": "", "specificationType": [ "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Missense variant at a codon with ≥2 missense variants classified pathogenic (by these guidelines), and predicts a different amino acid change.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "008", "instructionsToUse": "", "specificationtype": [ "Clarification" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts a different amino acid change.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0048", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637696" }, { "entContent": { "label": "BP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0206", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0204", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0075", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0205", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0082", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Missense variant in gene where only LOF causes disease", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637697" }, { "entContent": { "label": "BS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0229", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0227", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0071", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Lack of segregation in ≥2 index case families (unrelated), when data is available for ≥2 informative meioses in each family.\nCaveat: must be ≥1 unaffected relative (LDL-C <50th centile) who is positive for the variant.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0228", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0077", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637698" }, { "entContent": { "label": "PM6", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0235", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0014", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0037", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0010", "instructionsToUse": "", "specificationType": [ "Clarification" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "See PS2 above.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0022", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637699" }, { "entContent": { "label": "PS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0240", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0021", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0050", "instructionsToUse": "", "specificationType": [ "Clarification" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Missense variant at the same codon as a variant classified pathogenic (by these guidelines), and predicts the same amino acid change.\nCaveat: there is no in silico predicted splicing impact for either variant.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0046", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0036", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637700" }, { "entContent": { "label": "BP2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0209", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0207", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0068", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0208", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0084", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "If a FH patient with a heterozygous phenotype has a pathogenic or likely pathogenic variant in LDLR (in trans), APOB or PCSK9, BP2 is applicable to any additional LDLR variants.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637701" }, { "entContent": { "label": "PS2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0241", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0016", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0051", "instructionsToUse": "", "specificationType": [ "Clarification" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "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/", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "004", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0043", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637702" }, { "entContent": { "label": "BP3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0212", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0210", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0074", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0211", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0081", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "In-frame deletions/insertions in a repetitive region without a known function", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637703" }, { "entContent": { "label": "PS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0242", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0031", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0052", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Variant meets Level 1 pathogenic functional study criteria. See Table 3.\n(1) Study of the whole LDLR cycle (LDLR expression/biosynthesis, LDL binding, and LDL internalization) performed in heterologous cells (with noendogenous LDLR) transfected with mutant plasmid. Assay result of <70% ofwild-type activity in either expression/biosynthesis, binding OR internalization.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0039", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant meets Level 2 pathogenic functional study criteria. See Table 3.\n(1) Study of a) only part of the LDLR cycle following Level 1 methodology, or b) whole or part of the LDLR cycle in true homozygous patient cells. A variant with assay results of <70% of wild type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n(2) RNA studies, using RNA extracted from heterozygous or true homozygous patient cells, where aberrant transcript is confirmed by sequencing and is quantified as >25% of total transcript from heterozygous cells or 50% of total transcript from homozygous cells.\n(3) Variants with two or more Level 3 functional studies (must be different assays); or any Level 3 functional study #1-4 performed by two or more independent labs with concordant results.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0045", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Variant meets Level 3 pathogenic functional study criteria. See Table 3.\n (1) Study of LDLR cycle (whole or part) in heterozygous patient cells, with assay results of <85% of wild-type activity in either LDLR expression/biosynthesis, LDL binding OR internalization.\n (2) Luciferase studies with transcription levels of <50% compared to wild-type (applicable to 5’UTR/promoter variants).\n (3) Minigene splicing assays with <10% wild-type transcript present where anaberrant transcript from the candidate variant is confirmed by sequencing.\n (4) High-throughput assays, which include alternative microscopy assays (e.g.,Thormaehlen et al., 2015), Multiplex Assays of Variant Effect (MAVE) (e.g.,Weile & Roth, 2018) and deep mutational scanning assays, can be considered here, only if assay has been validated with a minimum of four pathogenic and four benign variant controls in LDLR. Note: % activity thresholds will be defined by the FH VCEP as more data becomes available.\n (5) RNA studies, using RNA extracted from heterozygous or homozygous patient cells, with aberrant transcript confirmed by sequencing (but without transcript quantification).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637704" }, { "entContent": { "label": "BP4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0215", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0213", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0066", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0214", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0080", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "REVEL score ≤0.5 (missense variants), or no predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637705" }, { "entContent": { "label": "PP1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0236", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0042", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0023", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Variant segregates with phenotype in ≥6 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0040", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant segregates with phenotype in 4-5 informative meioses in ≥1 family. Must include ≥2 affected relatives (LDL-C >75th centile) with the variant.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0060", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Variant segregates with phenotype in 2-3 informative meioses in ≥1 family. Must include ≥1 affected relative (LDL-C >75th centile) with the variant.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637706" }, { "entContent": { "label": "PS4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0243", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0029", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0053", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "Variant is found in ≥10 unrelated FH cases (FH diagnosis met by validated clinical criteria).\nCaveat: variant must also meet PM2", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0057", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant is found in 6-9 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0032", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Variant is found in 2-5 unrelated FH cases (FH diagnosis made by validated clinical criteria).\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637707" }, { "entContent": { "label": "PVS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0245", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0017", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "See PVS1 flow diagram (Figure 1).", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0020", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "See PVS1 flow diagram (Figure 1).", "type": "EvidenceLineStrength" }, { "applicability": "Applicable as originally described", "id": "0026", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Strength" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "See PVS1 flow diagram (Figure 1).", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "001", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637708" }, { "entContent": { "label": "BP5", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0218", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0216", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0073", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0217", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0078", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Variant found in a case with an alternate molecular basis for disease", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637709" }, { "entContent": { "label": "BA1", "strengthDescriptor": [ { "applicability": "Applicable with VCEP specification", "id": "0087", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "Variant has a PopMax FAF ≥0.005 (0.5%) in gnomAD.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0201", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0202", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0203", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0089", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637710" }, { "entContent": { "label": "PP2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0237", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0049", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0033", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0034", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0061", "instructionsToUse": "", "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637711" }, { "entContent": { "label": "PP3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0238", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0024", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0019", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0025", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0062", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "REVEL score ≥0.75 (missense variants), or predicted impact to splicing using MaxEntScan (see Fig. 2 for suggested thresholds).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637712" }, { "entContent": { "label": "BP7", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0221", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0219", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0065", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0220", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0079", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "Variant is synonymous.\nCaveat: variant must also meet BP4 (i.e. no predicted impact on splicing).", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637713" }, { "entContent": { "label": "PP4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0239", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "002", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "005", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0018", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0063", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "Any LDLR variant identified in an FH patient [diagnosis based on validated clinical criteria, e.g. Dutch Lipid Clinic Network (≥6), Simon Broome possible/definite), MEDPED], after alternative causes of high cholesterol are excluded.\nCaveat: variant must also meet PM2.", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637714" }, { "entContent": { "label": "PM1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0230", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0015", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0028", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "006", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Missense variant located in exon 4, or a missense change in one of 60 highly conserved cysteine residues (listed in Supp. Table 4). Caveat: variant must also meet PM2.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0054", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637715" }, { "entContent": { "label": "PM2", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0231", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0044", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0013", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "0011", "instructionsToUse": "", "specificationType": [ "Disease-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Variant has a PopMax MAF ≤0.0002 (0.02%) in gnomAD. Consider exceptions for known founder variants.", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0030", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637716" }, { "entContent": { "label": "BS1", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0090", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0222", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "120", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Gene-specific" ], "status": "approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "Allele frequency is >=0.02% based on the filtering allele frequency (FAF) in ExAC provided there is no conflicting information", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0223", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0086", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637772" }, { "entContent": { "label": "PM3", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0232", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0038", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0058", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "007", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0027", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637773" }, { "entContent": { "label": "BS2", "strengthDescriptor": [ { "applicability": "Not Applicable for this VCEP", "id": "0091", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000357", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0224", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0069", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000328", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0098", "instructionsToUse": "", "status": "not approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000699", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not Applicable for this VCEP", "id": "0076", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000327", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637774" }, { "entContent": { "label": "PM4", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0233", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0012", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "SEPIO:0000220", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0035", "instructionsToUse": "", "status": "not approved", "strength": "Strong", "strengthSepioID": "SEPIO:0000330", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "108", "instructionsToUse": "", "specificationType": [ "Disease-specific", "Gene-specific" ], "status": "approved", "strength": "Moderate", "strengthSepioID": "SEPIO:0000216", "text": "Protein length changes due to in-frame deletions/insertions of any size in a non-repeat region or stop-loss variants", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0059", "instructionsToUse": "", "status": "not approved", "strength": "Supporting", "strengthSepioID": "SEPIO:0000329", "text": "", "type": "EvidenceLineStrength" } ] }, "ldhId": "135637775" }, { "entContent": { "label": "BS3", "strengthDescriptor": [ { "applicability": "Not applicable", "id": "0226", "instructionsToUse": "", "status": "not approved", "strength": "Stand Alone", "strengthSepioID": "SEPIO:0000325", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Not applicable", "id": "0225", "instructionsToUse": "", "status": "not approved", "strength": "Very Strong", "strengthSepioID": "", "text": "", "type": "EvidenceLineStrength" }, { "applicability": "Applicable with VCEP specification", "id": "122", "instructionsToUse": "", "specificationType": [ "No change" ], "status": "approved", 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