{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/807b1008-f3f9-4267-96c0-1bbbc7a587ed/doc/sepio/version/2.2.0", "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:0015630", "id": "MONDO:0015630", "label": "von Willebrand disease type 2M", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/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": "2025/10/10", "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/CA228555/MONDO:0015630/081/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "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 (bleeding score of 7) as well as laboratory phenotypes that included a normal multimer pattern, low VWF:RCo/VWF:Ag ratio (0.67), and abnormal collagen binding assay, which together are highly specific for VWD type 2M. (PP4_moderate, PMID: 28083987). Please note that the multimer pattern did not lack high-molecular weight forms, but was visibly smeary, similar to the p.Arg1315Cys and p.Arg1374Cys variants (PMID: 26988807).", "contributionDate": { "date": "2025/10/10", "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": "CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/ei/1/1679", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2025/10/10", "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/CA228555/MONDO:0015630/081/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2025/10/10", "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": "CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/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": "2025/10/10", "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/CA228555/MONDO:0015630/081/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "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 0.712, which is above the ClinGen VWD VCEP threshold of >0.644 and predicts a damaging effect on VWF function (PP3). The computational splicing predictor SpliceAI gives a score of 0.00 for all splicing types, indicating that the variant has no impact on splicing.", "contributionDate": { "date": "2025/10/10", "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": "CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/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": "2025/10/10", "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/CA228555/MONDO:0015630/081/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "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 allele frequency in gnomAD v4.1 is 0.00005281 (8/74886 alleles) in the African/African American population, which is lower than the ClinGen VWD VCEP threshold (<0.0001), meeting this criterion (PM2_Supporting).", "contributionDate": { "date": "2025/10/10", "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": "CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/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": "2025/10/10", "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/CA228555/MONDO:0015630/081/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "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 in the same codon, NM_000552.5(VWF):c.4196G>A (p.Arg1399His), has been reported. This variant has been classified as VUS by the ClinGen VWD VCEP and is not considered here to avoid circularity.", "contributionDate": { "date": "2025/10/10", "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": "CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/el/0/1657", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228555/MONDO:0015630/081/ei/1/1658", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2025/10/10", "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/CA228555/MONDO:0015630/081/el/0/1657/1659", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "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 at least 10 probands with phenotypes meeting the laboratory phenotype requirements of type 2M PP4 criteria, in addition to the proband used for the PP4_Moderate code (PS4_Very Strong; PMID: 17000885, PMID: 26988807, PMID: 35452508, PMID: 34758185, Internal lab contributors).", "contributionDate": { "date": "2025/10/10", "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": "CA228555/MONDO:0015630/081/ci/CA228555/MONDO:0015630/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1657/1659", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/1/1658", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081/0/1657", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228555/MONDO:0015630/081", "metadata": { "created": "2025-10-10T19:46:57.054Z", "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": "Fri, 10 Oct 2025 19:46:56 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "2.2.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "807b1008-f3f9-4267-96c0-1bbbc7a587ed", "variant": { "@id": "https://reg.genome.network/allele/CA228555", "id": "CAR:CA228555", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000552.5:c.4195C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000552.5(VWF):c.4195C>T (p.Arg1399Cys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-02T03:18:24.310Z" } }, "status": { "code": 200, "name": "OK" } }