{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/2e8f631e-ae1d-42cc-b3b0-ebac2b007066/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1807907463", "label": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DYSF Version 2.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.0.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0015152", "id": "MONDO:0015152", "label": "autosomal recessive limb-girdle muscular dystrophy", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/ei/1/1739", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA275155/MONDO:0015152/180/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "This variant has been detected in a homozygous state in multiple individuals with a clinical diagnosis or suspicion of LGMD and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 33250842; PP4_Strong).", "contributionDate": { "date": "2026/2/17", "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": "CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/el/0/1588", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/ei/1/1589", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA275155/MONDO:0015152/180/el/0/1588/1590", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Tyr1041Cys protein did reach the cell membrane, indicating no impact on this aspect of protein function (PMID: 35028538).", "contributionDate": { "date": "2026/2/17", "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": "CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1588/1590", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/1/1589", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1588", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/el/0/1780", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/ei/1/1781", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA275155/MONDO:0015152/180/el/0/1780/1782", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "No other potentially LP/P missense variants at this position identified.", "contributionDate": { "date": "2026/2/17", "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": "CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1780/1782", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/1/1781", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1780", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/ei/1/1799", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA275155/MONDO:0015152/180/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.00013 (6/91074 South Asian chromosomes), which is higher than the VCEP threshold for PM2_Supporting (0.0001) (PM2_Supporting not met).", "contributionDate": { "date": "2026/2/17", "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": "CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA275155/MONDO:0015152/180/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The computational predictor REVEL gives a score of 0.95, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3).\n\nspliceAI 0", "contributionDate": { "date": "2026/2/17", "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": "CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/el/0/1825", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/ei/1/1826", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA275155/MONDO:0015152/180/el/0/1825/1827", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": " Immunofluorescence and 2-A assays of dysferlin membrane localization in HEK293T cells showed the Tyr1014Cy protein did not reach the cell membrane, indicating an impact on protein function (PMID: 35028538) (PS3_Moderate). ", "contributionDate": { "date": "2026/2/17", "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": "CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1825/1827", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/1/1826", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1825", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA275155/MONDO:0015152/180/ei/1/1652", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/2/17", "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/CA275155/MONDO:0015152/180/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "This variant has been detected in at least 15 individuals with features consistent with LGMD or dysferlinopathy (PMID: 35723113, 33250842, 30564623, 20544924, 37564451; Jain Foundation Dysferlin Registry internal data communication), 10 of whom were determined to be homozygous (capped at 1 pt, PMID: 35723113, 33250842, 30564623, 20544924, 37564451; Jain Foundation Dysferlin Registry internal data communication). It was also reported in unconfirmed phase with a Pathogenic variant in at least two cases (NM_003494.4: c.5526-1G>A, 0.5 pts, PMID: 20544924; NM_003494.4: c.3327_3328del p.(Phe1110CysfsTer3), 0.5 pts, PMID: 35723113) (PM3_Strong).\n\nscored: \nhomozygous: capped at 1.0 pt\nc.5526-1G>A: unconfirmed phase, independently P, 0.5 pts; not in gnomAD v2 so cannot assess co-occurrence\nc.3327_3328del: unconfirmed phase, independently P, 0.5 pts; not in gnomAD v2 so cannot assess co-occurrence \n\nunscored:\nc.3658C>T p.(Q1220X): unconfirmed phase, 0.5 pts if P\nc.6119G>A p.(Trp2040Ter): unknown phase, 0.5 pts if P\n\n\nJain Foundation Dysferlin Registry participants: 20 homozygotes, 11 presumed compound het in total but some duplicate reports and some without any phenotype data\n\nadditional potential compound het cases:\nRegistry ID 813\nc.5526-1G>A in unconfirmed phase; presume duplicate with Rosales et al. (2010)\nNationwide Children's Hospital\ndisease range dysferlin expression by blood monocyte assay\n\nRegistry ID 7460\nc.3327_3328delGT in unknown phase\nPerkin Elmer focused WES (duplicate with Khadilkar)?\nno phenotype details\n\nRegistry ID 7647\nc.2419C>T p.(Gln807X) in unknown phase\nDLE Human Genetics and Rare Diseases\nno phenotype details\n\nRegistry ID 8107\nc.4638+1G>A in unknown phase\nPerkin Elmer focused WES\nno phenotype details\n\nRegistry ID 8004\nc.5713C>T p.(Arg1905Ter) in unknown phase\nCAMDMD\nno phenotype details\n\nRegistry ID 7999\nc.2419C>T p.(Gln807Ter) in unknown phase\nKnown Mutation\nno phenotype details\n\nRegistry ID 8080\nc.5341-1G>A in unknown phase \nPerkin Elmer focused WES\nno phenotype details\n\nRegistry ID 1704\nc.3658C>T p.(Q1220X) in unknown phase\nTDM (Therapeutic Drug Monitoring); same variant as Nallamilli case and presumed duplicate (TDM I think just does blood monocyte assay)\ndisease range dysferlin by blood monocyte assay\n\nRegistry ID 8224\nc.2810+5G>A in unknown phase\nInvitae\nno phenotype details\n\n\n", "contributionDate": { "date": "2026/2/17", "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": "CA275155/MONDO:0015152/180/ci/CA275155/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA275155/MONDO:0015152/180", "metadata": { "created": "2026-02-17T19:01:59.489Z", "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": "Tue, 17 Feb 2026 19:01:59 -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": "2e8f631e-ae1d-42cc-b3b0-ebac2b007066", "variant": { "@id": "https://reg.genome.network/allele/CA275155", "id": "CAR:CA275155", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001130987.2:c.3095A>G" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001130987.2(DYSF):c.3095A>G (p.Tyr1032Cys)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-30T00:44:49.952Z" } }, "status": { "code": 200, "name": "OK" } }