{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/e79733a4-e6ed-4858-ace3-45c65283a72e/doc/sepio/version/1.0.0", "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/CA8643646/MONDO:0015152/189/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/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": "2026/5/7", "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/CA8643646/MONDO:0015152/189/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8643646/MONDO:0015152/189/ci/CA8643646/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": "At least one patient with this variant and a second presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness and significantly reduced or absent expression of alpha-sarcoglycan in skeletal muscle, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 39755676). ", "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": "CA8643646/MONDO:0015152/189/ci/CA8643646/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/ei/1/1718", "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/CA8643646/MONDO:0015152/189/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8643646/MONDO:0015152/189/ci/CA8643646/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 detected in at least six individuals with limb-girdle muscular dystrophy, including in a homozygous state in 5 patients (1 pt, PMID: 35416532, 39755676; International Centre for Genomic Medicine in Neuromuscular Diseases internal data communication) (PM3).\n\nEurofins Ntd Llc (ga)\nAccession: SCV000331524.5\n1 homozygote \n\nLabcorp Genetics (formerly Invitae), Labcorp\nAccession: SCV000649768.8\nobserved in individuals with clinical features of limb-girdle muscular dystrophy (PMID: 35116532; internal data)\n\nPreventionGenetics, part of Exact Sciences\nAccession: SCV004716399.2\nAt PreventionGenetics, we have observed this variant with a second SGCA variant in a patient tested for metabolic myopathy (internal data).\n\nNeuberg Centre For Genomic Medicine, NCGM\nAccession: SCV004047074.3\n1 affected observation\nSalient Features : Difficulty in getting up from a squatting position since the age of 10 Younger brother with similar complaint Clinical suspicion : Limb Girdle Muscular Dystrophy\n(India)", "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": "CA8643646/MONDO:0015152/189/ci/CA8643646/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/el/0/1765", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/ei/1/1766", "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/CA8643646/MONDO:0015152/189/el/0/1765/1767", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8643646/MONDO:0015152/189/ci/CA8643646/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": "c.37+1G>T\ndonor loss 0.7 (alt 0 vs 0.19 for curated variant)\nstrengthens same two alternative donors as curated variant, but strongest alternative donor for comparison variant is at a different position than the strongest alternative for the curated variant\nboth alternative donors are out of frame\n\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": "CA8643646/MONDO:0015152/189/ci/CA8643646/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1765/1767", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/1/1766", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1765", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/el/0/1612", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/ei/1/1613", "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/CA8643646/MONDO:0015152/189/el/0/1612/1614", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8643646/MONDO:0015152/189/ci/CA8643646/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 NM_000023.4: c.37+6T>C variant in SGCA, occurs outside the canonical splice donor site (+/- 1,2) of intron 1. SpliceAI gives a delta score of 0.51 for loss of the canonical donor and of 0.25 for gain of a cryptic donor 59 bp into the intron. RNA-seq on a LGMD patient carrying the variant and a second missense variant (c.725T>C, p.Val242Arg) showed a reduced number of reads with normal splicing at the junction compared to a control sample. The patient sample also showed a 59-bp partial intron 1 retention that was not observed in the control sample and introduces a frameshift with nonsense mediated decay expected (PMID: 39755676; PVS1_RNA_Moderate).\n\nThe score was reduced given inability to quantify the proportion of transcripts with altered splicing. ", "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": "CA8643646/MONDO:0015152/189/ci/CA8643646/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1612/1614", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/1/1613", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1612", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/el/0/1678", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/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": "2026/5/7", "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/CA8643646/MONDO:0015152/189/el/0/1678/1680", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8643646/MONDO:0015152/189/ci/CA8643646/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 variant has been reported to segregate with autosomal recessive limb girdle muscular dystrophy in 3 affected family members from one family (PP1, capped with PP4_Strong; International Centre for Genomic Medicine in Neuromuscular Diseases internal data communication).", "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": "CA8643646/MONDO:0015152/189/ci/CA8643646/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1678/1680", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/1/1679", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1678", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA8643646/MONDO:0015152/189/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": "2026/5/7", "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/CA8643646/MONDO:0015152/189/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA8643646/MONDO:0015152/189/ci/CA8643646/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 upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.000085 (3/91042 South Asian alleles), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, and therefore meets this criterion.", "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": "CA8643646/MONDO:0015152/189/ci/CA8643646/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA8643646/MONDO:0015152/189", "metadata": { "created": "2026-05-07T16:01:52.518Z", "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 16:01:52 -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": "e79733a4-e6ed-4858-ace3-45c65283a72e", "variant": { "@id": "https://reg.genome.network/allele/CA8643646", "id": "CAR:CA8643646", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000023.4:c.37+6T>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000023.4(SGCA):c.37+6T>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-02T04:37:22.413Z" } }, "status": { "code": 200, "name": "OK" } }