{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/a6da2b92-5e98-4a14-981c-3a5872a0a75b/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/CA383520272/MONDO:0015628/081/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/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": "2024/8/13", "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/CA383520272/MONDO:0015628/081/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383520272/MONDO:0015628/081/ci/CA383520272/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 is absent from gnomAD v4.1 (PM2_Supporting).", "contributionDate": { "date": "2024/8/13", "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": "CA383520272/MONDO:0015628/081/ci/CA383520272/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/el/0/1579", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/ei/1/1580", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2024/8/13", "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/0078", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000327", "id": "SEPIO:0000327", "label": "Benign Supporting" }, "id": "0078", "label": "BP5", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/el/0/1579/1581", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383520272/MONDO:0015628/081/ci/CA383520272/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 patient had three heterozygous missense mutations (R202W, C849Y, and R1583Q) in the VWF gene. R1583Q is classified Likely Benign by the VWD VCEP. R202W (ClinVar 619940 VUS) is not yet evaluated and classification of the variant would not affect the likely pathogenic classification of Cys849Tyr at this time.", "contributionDate": { "date": "2024/8/13", "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": "CA383520272/MONDO:0015628/081/ci/CA383520272/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1579/1581", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/1/1580", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1579", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2024/8/13", "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/0052", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0052", "label": "PS3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383520272/MONDO:0015628/081/ci/EV000001692", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "Multimerization assay performed with the NM_000552.5(VWF):c.2546G>A (p.Cys849Tyr) recombinant mutant and controls including wild-type vWF expressed by COS-7 cells showed absent higher-MW multimers, indicating that this variant has a damaging effect on protein function consistent with the multimerization defect observed in the proband (PS3_Supporting, PMID: 19422453, Figure 5). One of the other variants in trans (p.Arg202Trp) also showed a severe multimerization defect, raising the possibility of a combined effect. The recombinant mutant protein also showed severely defective binding to Factor VIII (Figure 7).", "contributionDate": { "date": "2024/8/13", "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": "CA383520272/MONDO:0015628/081/ci/EV000001692", "traceableAuthorStatement": "https://www.ncbi.nlm.nih.gov/pubmed/19422453", "type": "CuratorInference" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/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": "2024/8/13", "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/CA383520272/MONDO:0015628/081/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383520272/MONDO:0015628/081/ci/CA383520272/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 0.579, which is below the ClinGen VWD VCEP PP3 threshold of >0.644 and does not predict a damaging effect on VWF function. However, the splicing predictor SpliceAI gives a delta score of 0.72 for donor loss (PP3), which has been functionally confirmed to result in an aberrant splicing product in an affected individual (Figure 3, PMID: 19422453).", "contributionDate": { "date": "2024/8/13", "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": "CA383520272/MONDO:0015628/081/ci/CA383520272/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA383520272/MONDO:0015628/081/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": "2024/8/13", "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/CA383520272/MONDO:0015628/081/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA383520272/MONDO:0015628/081/ci/CA383520272/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 VWF:RCo/VWF:Ag ratio (0.51), and loss of high molecular weight multimers, which together are highly specific for VWD type 2A. (PP4, PMID: 19422453, PMID: 35452508). Additional consistent phenotypes were also reported in the patient including low VWF activity indicated by mildly impaired binding of factor VIII to VWF and impaired von Willebrand factor collagen binding activity (59 IU/dL), normal platelet count, FVIII activity consistent with VWF antigen, and an impaired RIPA assay.", "contributionDate": { "date": "2024/8/13", "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": "CA383520272/MONDO:0015628/081/ci/CA383520272/MONDO:0015628/081.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081/0/1633", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA383520272/MONDO:0015628/081", "metadata": { "created": "2024-09-28T05:30:20.867Z", "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 05:30:20 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "a6da2b92-5e98-4a14-981c-3a5872a0a75b", "variant": { "@id": "https://reg.genome.network/allele/CA383520272", "id": "CAR:CA383520272", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000552.5:c.2546G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000552.5(VWF):c.2546G>A (p.Cys849Tyr)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-31T06:52:35.383Z" } }, "status": { "code": 200, "name": "OK" } }