{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/7451c2f1-7e09-46f1-be83-ab46032458b5/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:0015628", "id": "MONDO:0015628", "label": "von Willebrand disease type 2A", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2025/5/9", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "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 laboratory phenotypes of very low VWF activity, low activity/VWF:Ag ratio, and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4_moderate, PMID 34532631). Additional consistent phenotypes were also reported in the patient, specifically, FVIII activity consistent with VWF antigen.\n", "contributionDate": { "date": "2025/5/9", "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": "CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/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": "2025/5/9", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "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 0.947, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3).\n", "contributionDate": { "date": "2025/5/9", "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": "CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/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": "2025/5/9", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "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 0.0000006195 (1/1180046 European non-Finnish population), which is lower than the ClinGen VWD VCEP threshold of <0.0001 for type 2A (PM2_Supporting).\n", "contributionDate": { "date": "2025/5/9", "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": "CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2025/5/9", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "Another missense variant NM_000552.5:c.3568T>C (p.Cys1190Arg) in the same codon has been classified as pathogenic for VWD type 2A by the ClinGen VWD VCEP (PM5). ", "contributionDate": { "date": "2025/5/9", "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": "CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/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": "2025/5/9", "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" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383510975/MONDO:0015628/081/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "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 6 additional probands meeting PP4 laboratory phenotype criteria (PS4; PMID 20351307, 32864553, 32803740, 34355501, 36696193, GoldVariantDatabase PersonalCommunication).", "contributionDate": { "date": "2025/5/9", "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": "CA383510975/MONDO:0015628/081/ci/CA383510975/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081/0/1735", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383510975/MONDO:0015628/081", "metadata": { "created": "2025-05-15T16:26:12.459Z", "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": "Thu, 15 May 2025 16:26:12 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "7451c2f1-7e09-46f1-be83-ab46032458b5", "variant": { "@id": "https://reg.genome.network/allele/CA383510975", "id": "CAR:CA383510975", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000552.5:c.3569G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000552.5(VWF):c.3569G>A (p.Cys1190Tyr)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T07:17:57.365Z" } }, "status": { "code": 200, "name": "OK" } }