{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://erepo.genome.network/evrepo/api/summary/classification/79ef832a-3ca0-4760-a3fd-221316a3f0f7/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1528062415", "label": "ClinGen von Willebrand Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VWF Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0019565", "id": "MONDO:0019565", "label": "hereditary von Willebrand disease", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0053", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0053", "label": "PS4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "This variant has been reported in 2 probands, 1 of whom has met PP4. PS4_Supporting cannot be applied because the second proband has not met PP4, and because it is not clear whether the two probands are unrelated (PMID: 28971901, PMID: 22315491).", "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0062", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0062", "label": "PP3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.143, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function. Additionally, the computational splicing predictor SpliceAI indicates that the variant has no impact on splicing.", "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0063", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0063", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "At least 1 patient with this variant displayed excessive mucocutaneous bleeding as well as a laboratory phenotype of low VWF:RCo/VWF:Ag ratio (0.62), which together are specific for VWD type 2M (PP4, PMID: 28971901). A second patient with this variant was diagnosed with VWD Type 1-2N but exhibited low VWF:Co (0.49) without a low VWF:RCo/VWF:Ag ratio (1), (PMID: 22315491). Both patients had the inconsistent feature of low FVIII activity (0.12-20) relative to VWF antigen (0.49-0.78), resulting in one publication flagging the patient / variant as having \"a discrepant phenotype-genotype correlation\" (PMID: 28971901). The presence of the D1472H variant was ruled out by the use of next-generation sequencing-based genotyping in both patients.", "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0030", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0030", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "The Grpmax filtering allele frequency in gnomAD v4.1 is 0.000008780 (based on 2/91076 alleles in the South Asian population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 (PM2_Supporting).", "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/ei/1/1685", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "criterion": { "@id": "https://obofoundry.org/sepio/clingen/0080", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000327", "id": "SEPIO:0000327", "label": "Benign Supporting" }, "id": "0080", "label": "BP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6402670/MONDO:0019565/081/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.143, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function (PP3).", "contributionDate": { "date": "2024/8/12", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA6402670/MONDO:0019565/081/ci/CA6402670/MONDO:0019565/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081/0/1684", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6402670/MONDO:0019565/081", "metadata": { "created": "2024-09-28T05:24:58.067Z", "note": "DISCLAIMER: While the data/content in this document is approved by ClinGen expert panel(s), the SEPIO schema presented here is an initial prototype and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema.", "producedAtUTC": "Sat, 28 Sep 2024 05:24:57 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26333-7", "id": "LN:LA26333-7", "label": "Uncertain Significance" }, "type": "VariantPathogenicityInterpretation", "uuid": "79ef832a-3ca0-4760-a3fd-221316a3f0f7", "variant": { "@id": "https://reg.genome.network/allele/CA6402670", "id": "CAR:CA6402670", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000552.5:c.3788C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000552.5(VWF):c.3788C>T (p.Ser1263Leu)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-05-14T15:25:28.065Z" } }, "status": { "code": 200, "name": "OK" } }