{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/d000f4f9-fefb-4a45-9939-a12016651e14/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1529372862", "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:0015631", "id": "MONDO:0015631", "label": "von Willebrand disease type 2N", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/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": "2025/1/8", "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/CA228314/MONDO:0015631/090/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "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 low FVIII activity and decreased VWF:FVIII binding, which is highly specific for VWD type 2N. (PP4_moderate, PMID: 12393698). The binding capacity of VWF:FVIIIB was found to be decreased both as an absolute value (11.9 U/dL versus normal range, 70-140 U/dL) and a ratio (0.23 versus normal > 0.75).\n", "contributionDate": { "date": "2025/1/8", "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": "CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/el/0/1684", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/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": "2025/1/8", "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/CA228314/MONDO:0015631/090/el/0/1684/1686", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "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 0.219, which is below the ClinGen VWD VCEP threshold of <0.290 and does not predict a damaging effect on VWF function. Additionally, the computational splicing predictor SpliceAI indicated that the variant has no impact on splicing (BP4). \n", "contributionDate": { "date": "2025/1/8", "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": "CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1684/1686", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/1/1685", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1684", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/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": "2025/1/8", "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/CA228314/MONDO:0015631/090/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "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 0.000007410 (based on 2/60034 alleles in the Admixed American population), which is lower than the ClinGen VWD VCEP threshold of <0.005 for type 2N VWD (PM2_Supporting).", "contributionDate": { "date": "2025/1/8", "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": "CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/ei/1/1718", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "contributionDate": { "date": "2025/1/8", "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/CA228314/MONDO:0015631/090/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "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 detected in at least 1 individual with VWF Type 2N (PMID: 12393698) This individual was compound heterozygous (confirmed in trans by parental testing) for this variant and the p.R854Q variant which was classified as pathogenic by the VCEP (1 PM3 points, PM3). ", "contributionDate": { "date": "2025/1/8", "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": "CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/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": "2025/1/8", "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/CA228314/MONDO:0015631/090/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "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(VWF):c.2279G>A (p.Arg760His)\n(ClinVar 31011, Pathogenic) in the same codon has not yet been classified by the ClinGen VWD VCEP. However, this variant is consistently associated with type 1 VWD. ", "contributionDate": { "date": "2025/1/8", "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": "CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/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": "2025/1/8", "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/CA228314/MONDO:0015631/090/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "Factor VIII binding assay performed with the p.Arg760Cys recombinant mutant and wt vWF expressed by FUR4BHK cells showed absent binding indicating that this variant has a damaging effect on protein function (PMID: 12393698 )(PS3).", "contributionDate": { "date": "2025/1/8", "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": "CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA228314/MONDO:0015631/090/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": "2025/1/8", "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/CA228314/MONDO:0015631/090/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50051_EP172323000528245", "id": "CG-PCER-AGENT:CG_50051_EP172323000528245", "type": "Agent" }, "comments": "PMID: 12393698\nFather carries variant, but has VWF:FVIIIB/VWF:Ag of 0.45. \n\n* Addition of PP1 would not change classification", "contributionDate": { "date": "2025/1/8", "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": "CA228314/MONDO:0015631/090/ci/CA228314/MONDO:0015631/090.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090/0/1678", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA228314/MONDO:0015631/090", "metadata": { "created": "2025-01-08T21:09:18.389Z", "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": "Wed, 08 Jan 2025 21:09:18 -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": "d000f4f9-fefb-4a45-9939-a12016651e14", "variant": { "@id": "https://reg.genome.network/allele/CA228314", "id": "CAR:CA228314", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000552.5:c.2278C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000552.5(VWF):c.2278C>T (p.Arg760Cys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-29T06:22:22.270Z" } }, "status": { "code": 200, "name": "OK" } }