{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/97530a61-603a-4523-afe2-1c7c833609ed/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/643243141", "label": "ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F8 Version 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0010602", "id": "MONDO:0010602", "label": "hemophilia A", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/ei/1/1679", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2024/7/11", "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/0060", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000329", "id": "SEPIO:0000329", "label": "Pathogenic Supporting" }, "id": "0060", "label": "PP1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "Potentially PP1_Strong based on the report of at least 2 male relatives of unrelated probands seen in PMID: 21751985. However, PP1 is not applied since pedigrees/exact relationships are not available.", "contributionDate": { "date": "2024/7/11", "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": "CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2024/7/11", "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/CA10568501/MONDO:0010602/071/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "Tyr365Cys has a REVEL score of 0.756, meeting the threshold for PP3 for F8 (>= 0.6). CADD score of 22.3 (threshold >= 21) also meets PP3.", "contributionDate": { "date": "2024/7/11", "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": "CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1735", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/ei/1/1736", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2024/7/11", "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/CA10568501/MONDO:0010602/071/el/0/1735/1737", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "More than 8 patients reported in the literature with the variant and inverse discrepant FVIII:C measured lower by OSA and in the normal range by TSA or CSA, meet F8 phenotype criteria. VWD was ruled out in proband from PMID: 19456877. Patients reported with this variant across the literature are noted to have mild HA based on FVIII:C1l; however, no significant bleeding abnormalities are noted. PS4_Very Strong is applied based on low factor VIII levels; however, it is noted that individuals may not be symptomatic.", "contributionDate": { "date": "2024/7/11", "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": "CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1735/1737", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/1/1736", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1735", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/ei/1/1805", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2024/7/11", "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/0070", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000328", "id": "SEPIO:0000328", "label": "Benign Strong" }, "id": "0070", "label": "BS1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "The variant is reported in gnomAD v2.1.1 at a frequency of 0.0001466 (12/81864 alleles with 6 hemizygotes) and in gnomAD v3 at a frequency of 0.0001388 (7/50445 alleles with 1 hemizygote) in the non-Finnish European population. The MAFs do not meer the BS1 threshold for F8 (>= 0.000167).", "contributionDate": { "date": "2024/7/11", "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": "CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1804", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/ei/1/1799", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2024/7/11", "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/0011", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0011", "label": "PM2", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "Tyr365Cys is reported in gnomAD with hemizygotes. 6 hemizygotes are noted in the NFE population in gnomAD v2.1.1. PM2 not met. However, PS4 is counted upon expert review. ", "contributionDate": { "date": "2024/7/11", "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": "CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1831", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/ei/1/1832", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2024/7/11", "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/0018", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "0018", "label": "PP4", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1831/1833", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "Male with mild hemophilia A with 11% factor VIII activity level who underwent full gene sequencing of F8 and F9 with deletion/duplication analysis.", "contributionDate": { "date": "2024/7/11", "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": "CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1831/1833", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/1/1832", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1831", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1615", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/ei/1/1616", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "contributionDate": { "date": "2024/7/11", "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/006", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000216", "id": "SEPIO:0000216", "label": "Pathogenic Moderate" }, "id": "006", "label": "PM1", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA10568501/MONDO:0010602/071/el/0/1615/1617", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50041_EP17152769886754", "id": "CG-PCER-AGENT:CG_50041_EP17152769886754", "type": "Agent" }, "comments": "Data from Mumford et al, 2002; PMID: 12139751 suggests that the Tyr365Cys variant results in impaired activation of the FVIII zymogen and faster decay compared to WT of the activated heterotrimer due to its location in the acidic a1 interdomain region and proximity to thrombin, FIXa, FXa, and APC cleavage sites. \"The Tyr365Cys variant is shown to result in impaired activation of the FVIII zymogen and faster decay compared to WT of the activated heterotrimer. The Tyr365 residue occurs in the acidic a1 interdomain, which is reported to minimize FVIIIa dissociation by stabilizing the A2 domain. Tyr365 is one of the tyrosine residues that is shown to be sulfated during post-translational modification (PMID: 1554716). Variants at this residue may be less efficiently cleaved by thrombin at Arg373 (PMID: 8051097). Arg336 is noted to be a cleavage site for FIXa, FXa and APC (PMID: 3082357). The a1 region is thought to be a key regulator in the inactivation of FVIIIa heterotrimer (PMID: 8349670) and to comprise a binding site for FXa (PMID: 8999906).\" Evidence is applied towards PM1, pending expert review.", "contributionDate": { "date": "2024/7/11", "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": "CA10568501/MONDO:0010602/071/ci/CA10568501/MONDO:0010602/071.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1615/1617", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/1/1616", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071/0/1615", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA10568501/MONDO:0010602/071", "metadata": { "created": "2024-09-28T04:59:47.919Z", "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 04:59:47 -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": "97530a61-603a-4523-afe2-1c7c833609ed", "variant": { "@id": "https://reg.genome.network/allele/CA10568501", "id": "CAR:CA10568501", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000132.3:c.1094A>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000132.3(F8):c.1094A>G (p.Tyr365Cys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-31T19:27:04.461Z" } }, "status": { "code": 200, "name": "OK" } }