{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/87f393fa-1b09-4af4-9687-8ee3aa108b19/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/CA222156/MONDO:0015152/180/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/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/CA222156/MONDO:0015152/180/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA222156/MONDO:0015152/180/ci/CA222156/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": "At least one of the patients with two presumed diagnostic DYSF variants had a clinical diagnosis of LGMD and absent dysferlin protein expression, which is highly specific for DYSF-related LGMD (PMID: 27602406; 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": "CA222156/MONDO:0015152/180/ci/CA222156/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/MONDO:0015152/180/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/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/CA222156/MONDO:0015152/180/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA222156/MONDO:0015152/180/ci/CA222156/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 identified in at least 10 unrelated individuals with LGMD (PMID: 195280, 27066573, 27602406, 30564623) including in a homozygous state in four patients, which includes a sibling pair, all without reported familial consanguinity (1.0 pt, PMID: 15469449, 27602406) and in unknown phase with a pathogenic variant in one patient (c.6124C>T p.(Arg2042Cys), 0.5 pts, PMID: 27602406). The variant was also identified in two affected siblings in a confirmed trans phase with a pathogenic variant (c.4886+1249G>T, 1.0 pt, PMID: 30564623) (PM3_Strong; PP1). ", "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": "CA222156/MONDO:0015152/180/ci/CA222156/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1651", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/MONDO:0015152/180/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/MONDO:0015152/180/ei/1/1595", "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/CA222156/MONDO:0015152/180/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA222156/MONDO:0015152/180/ci/CA222156/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 NM_003494.4: c.3444_3445delTGinsAA p.(Tyr1148Ter) variant in DYSF, which is also known as NM_001130987.2: c.3498_3499delinsAA p.(Tyr1166Ter), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 32/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).\n\nSplice AI: 0.66 (Acceptor gain) - out-of-frame", "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": "CA222156/MONDO:0015152/180/ci/CA222156/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/MONDO:0015152/180/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/MONDO:0015152/180/ei/1/1679", "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/CA222156/MONDO:0015152/180/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA222156/MONDO:0015152/180/ci/CA222156/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 was identified in two sets of siblings, one in a homozygous state and the second in a compound heterozygous state with a pathogenic variant.\n\nGiven PP4_Strong is applied, PP1 is capped at supporting.", "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": "CA222156/MONDO:0015152/180/ci/CA222156/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/MONDO:0015152/180/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA222156/MONDO:0015152/180/ei/1/1637", "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/CA222156/MONDO:0015152/180/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA222156/MONDO:0015152/180/ci/CA222156/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 filtering allele frequency of this variant is 0.000028251 in gnomAD v4.1.0 (the upper threshold of the 95% CI of 22/1112002 European (non-Finnish) exome chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). \n\nThis variant is an MNV and the combined frequency is not present in gnomAD. However, the individual variants are present and the frequency was obtained from one of them (c.3444T>A p.(Tyr1148Ter)). Of note, available bam files show presence of both variants.", "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": "CA222156/MONDO:0015152/180/ci/CA222156/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA222156/MONDO:0015152/180", "metadata": { "created": "2026-02-17T18:16:02.978Z", "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 18:16:02 -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": "87f393fa-1b09-4af4-9687-8ee3aa108b19", "variant": { "@id": "https://reg.genome.network/allele/CA222156", "id": "CAR:CA222156", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001130987.2:c.3498_3499delinsAA" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001130987.2(DYSF):c.3498_3499delinsAA (p.Tyr1166_Gly1167delinsTer)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T23:48:24.930Z" } }, "status": { "code": 200, "name": "OK" } }