{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/1d8c5ad9-8453-4ae4-8c22-1b4c7b044189/doc/sepio/version/2.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/135637577", "label": "ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2,\nKCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2.0", "type": "VariantPathogenicityInterpretationGuideline", "url": "https://clinicalgenome.org/site/assets/files/7814/clingen_hl_acmg_specifications_cdh23_coch_gjb2_kcnq4_myo6_myo7a_slc26a4_tecta_ush2a_v2.pdf", "version": "2.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0019497", "id": "MONDO:0019497", "label": "nonsyndromic genetic deafness", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "contributionDate": { "date": "2026/9/30", "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/CA6904317/MONDO:0019497/005/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "comments": "Bioinformatic analysis was used to predict the effect of the p.Val37Ala variant on GJB2 and molecular modeling determined that there may be a loss of protein structure. However, because no in vitro or in vivo experiments were done, this was not counted towards PS3.", "contributionDate": { "date": "2026/9/30", "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": "CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/el/0/1621", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/ei/1/1622", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "contributionDate": { "date": "2026/9/30", "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/0056", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0056", "label": "PM5", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/el/0/1621/1623", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "comments": "Two different pathogenic missense variants (p.Val37Ile and p.Val37Phe) have been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5_Strong, p.Val37Ile ClinVar Variation ID 17023, PMID 31160754; p.Val37Phe ClinVar Variation ID:179256 PMID: 37108562)).", "contributionDate": { "date": "2026/9/30", "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": "CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1621/1623", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/1/1622", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1621", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/ei/1/1652", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "contributionDate": { "date": "2026/9/30", "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/0058", "defaultStrength": { "@id": "https://obofoundry.org/sepio/SEPIO:0000330", "id": "SEPIO:0000330", "label": "Pathogenic Strong" }, "id": "0058", "label": "PM3", "type": "Criterion" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "comments": "This variant has been identified in 11 patients who did not harbor a second variant in GJB2 (PMID 21287563, 17666888, 15365987, GeneDx internal data, Invitae internal data), but has also been detected in two patients in trans with pathogenic/likely pathogenic variants c.167delT (p.Leu56Argfs*26), c.132G>A (p.Trp44Ter) and one predicted in trans with pathogenic/likely pathogenic c.647_650delGATA (p.Arg216Ilefs*17) (2.5 points, PM3_Strong met; Partners Laboratory for Molecular Medicine SCV000967620.2, Molecular Otolaryngology and Renal Research Laboratories internal data).", "contributionDate": { "date": "2026/9/30", "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": "CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/ei/1/1799", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "contributionDate": { "date": "2026/9/30", "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/CA6904317/MONDO:0019497/005/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "comments": " The highest population minor allele frequency in gnomAD v4.1.1 is 0.0337% (25/74924 alleles-African/African American, PM2_Supporting, BA1, and BS1 not met).", "contributionDate": { "date": "2026/9/30", "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": "CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA6904317/MONDO:0019497/005/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "contributionDate": { "date": "2026/9/30", "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/CA6904317/MONDO:0019497/005/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50007_EP155190799758139", "id": "CG-PCER-AGENT:CG_50007_EP155190799758139", "type": "Agent" }, "comments": "The computational predictor REVEL yields a score of 0.675 (PP3 not met).", "contributionDate": { "date": "2026/9/30", "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": "CA6904317/MONDO:0019497/005/ci/CA6904317/MONDO:0019497/005.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005/0/1747", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA6904317/MONDO:0019497/005", "metadata": { "created": "2026-10-15T19:09:26.998Z", "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 Oct 2026 19:09:26 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "2.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "1d8c5ad9-8453-4ae4-8c22-1b4c7b044189", "variant": { "@id": "https://reg.genome.network/allele/CA6904317", "id": "CAR:CA6904317", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_004004.6:c.110T>C" } ], "preferred": true }, { "alleleName": [ { "name": "NM_004004.6(GJB2):c.110T>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_004004.6(GJB2):c.110T>C (p.Val37Ala)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-01T19:05:38.791Z" } }, "status": { "code": 200, "name": "OK" } }