{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/af9bb602-e298-4166-9ed5-e45fa86bb7ce/doc/sepio/version/2.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1812104356", "label": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SGCA 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/CA245046/MONDO:0015152/189/el/0/1777", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/ei/1/1778", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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/CA245046/MONDO:0015152/189/el/0/1777/1779", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "The Grpmax FAF (the lower bound of the 95% confidence interval of the maximum credible genetic ancestry group allele frequency) is 0.0023 in gnomAD v4.1.1 (123/44882 East Asian chromosomes), which is higher than the ClinGen Limb Girdle Muscular Dystrophy Expert Panel threshold (0.002) for BA1. However, this variant appear to be one of the most commonly described SGCA variants reported in Japanese patients, where it has been associated with a mild phenotype (PMID: 39755676), and the VCEP opted not to apply this code (BA1 exception). \n\nNo homozygotes in Total\n\nfrom Vijay about co-occurrence in gnomAD v2: \"it’s seen in trans with only 1 other ClinVar variant (a B/LB variant). It’s not seen in trans with any ClinVar P/LP variants. We don’t yet have a statistic to tell you how “unlikely” this is (i.e., an equivalent of an “observed/expected” metric), but we’re working on it. So take it with a grain of salt for now, but yes I think it’s reasonable that this could be a hypomorphic variant that’s tolerated as a homozygote but not as a compound het with a more damaging variant.\"\n\nIn Shimazaki et al., 30 Japanese patients with SGCA variants: 7/60 alleles with c.320C>T (p.Ala107Val) = MAF 11.7% vs FAF 0.23% for East Asian (50x higher), but this cohort had additional requirement of 2 SGCA variants + reduced protein expression. They did not do haplotype analysis for this variant.\n", "contributionDate": { "date": "2026/5/7", "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": "CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1777/1779", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/1/1778", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1777", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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/CA245046/MONDO:0015152/189/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "Indeterminate result in an in vitro assay of membrane localization of the sarcoglycan complex (Washington University internal data).\n\nfunctional score in WashU assay: -0.33 (cut-off for PS3_Moderate: -0.5)\nlargely concordant result in Lek/Yale assay: -1.5 (no cut-off determined)", "contributionDate": { "date": "2026/5/7", "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": "CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/el/0/1804", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/ei/1/1805", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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/CA245046/MONDO:0015152/189/el/0/1804/1806", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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": "CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1804/1806", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/1/1805", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1804", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/el/0/1798", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/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": "2026/5/7", "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/CA245046/MONDO:0015152/189/el/0/1798/1800", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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": "CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1798/1800", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/1/1799", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1798", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/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": "2026/5/7", "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/CA245046/MONDO:0015152/189/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "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 0.864, which is above the threshold of 0.70, evidence that correlates with impact to SGCA function (PP3).", "contributionDate": { "date": "2026/5/7", "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": "CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/el/0/1633", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/ei/1/1634", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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/CA245046/MONDO:0015152/189/el/0/1633/1635", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "comments": "All of the reported compound heterozygous Japanese patients had significantly reduced expression of sarcoglycan in skeletal muscle by immunohistochemistry and some were also reported to have limb girdle muscle weakness. However, progression in these patients was not clearly described. Some patients presented with only hyperCKemia (PMID: 39755676).\n\nRetrospective study with limited individual phenotype details. Patients seem to have been identified based on genetic test and protein expression findings rather than clinically. ", "contributionDate": { "date": "2026/5/7", "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": "CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1633/1635", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/1/1634", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1633", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/el/0/1669", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA245046/MONDO:0015152/189/ei/1/1670", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2026/5/7", "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/CA245046/MONDO:0015152/189/el/0/1669/1671", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "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 reported confirmed in trans with another SGCA variant in 8 unrelated East Asian patients with reduced sarcoglycan protein expression in skeletal muscle and clinical features consistent with LGMD or sarcoglycanopathy, although it was typically associated with a mild presentation (PMID: 39755676, 30764848, 28403181). Five patients had a likely pathogenic or pathogenic variant confirmed in trans (c.229C>T p.(Arg77Cys), 1.0 pt x3, PMID: 39755676; c.662G>C p.(Arg221Pro), 1.0 pt, PMID: 39755676; c.661C>T p.(Arg221Cys), 1.0 pt, PMID: 30764848, 28403181) (PM3_Very Strong).\n\nc.38-2A>C\nc.229C>T p.(Arg77Cys) x3: VCEP P\nc.271G>A p.(Gly91Ser): LP/P in ClinVar\nc.409_410delinsCCTGGTGCGCAGCCAGG, p.(E137delinsPGAQPG)\nc.662G>C p.(Arg221Pro): VCEP LP\nc.661C>T p.(Arg221Cys): VCEP LP\n\nc.38-2A>C, p.(E137delinsPGAQPG), c.662G>C p.(Arg221Pro): absent gnomAD v2\nc.229C>T p.(Arg77Cys), c.271G>A p.(Gly91Ser), c.661C>T (p.Arg221Cys): predicted on different haplotypes in gnomAD v2", "contributionDate": { "date": "2026/5/7", "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": "CA245046/MONDO:0015152/189/ci/CA245046/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1669/1671", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/1/1670", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189/0/1669", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA245046/MONDO:0015152/189", "metadata": { "created": "2026-05-07T14:59:46.567Z", "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, 07 May 2026 14:59:46 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "2.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26332-9", "id": "LN:LA26332-9", "label": "Likely Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "af9bb602-e298-4166-9ed5-e45fa86bb7ce", "variant": { "@id": "https://reg.genome.network/allele/CA245046", "id": "CAR:CA245046", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000023.4:c.320C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000023.4(SGCA):c.320C>T (p.Ala107Val)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-28T07:53:59.046Z" } }, "status": { "code": 200, "name": "OK" } }