{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/a77a5d53-75ac-4487-aebe-2d62b25b9cf8/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/CA120423/MONDO:0015152/189/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/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/CA120423/MONDO:0015152/189/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA120423/MONDO:0015152/189/ci/CA120423/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 another presumed diagnostic SGCA variant displayed progressive limb girdle muscle weakness and significantly reduced alpha-sarcoglycan protein expression, which is highly specific for SGCA-related LGMD (PP4_Strong; PMID: 29382405).\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": "CA120423/MONDO:0015152/189/ci/CA120423/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/MONDO:0015152/189/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/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/CA120423/MONDO:0015152/189/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA120423/MONDO:0015152/189/ci/CA120423/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 0.596, which is below the threshold of 0.7 (PP3 not met). \n\nLocated 7 amino acids to the end of the exon. \nSpliceAI: 0.0100\nGenie: \n NIF-ML Score: 0.0\n Benign: 100%\n SpliceVault Top-10: Exon skipping of exon 3 seems to occur naturally and frequently according to GTEx and SRA.\n Conclusion:\n -Variant does not affect the assessed donor region (-4 to +8).\n -No cryptic Risk", "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": "CA120423/MONDO:0015152/189/ci/CA120423/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/MONDO:0015152/189/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/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/CA120423/MONDO:0015152/189/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA120423/MONDO:0015152/189/ci/CA120423/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 0.000037447 (33/1178322 European (non-Finnish) 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": "CA120423/MONDO:0015152/189/ci/CA120423/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/MONDO:0015152/189/el/0/1825", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/MONDO:0015152/189/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": "2026/5/7", "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/CA120423/MONDO:0015152/189/el/0/1825/1827", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA120423/MONDO:0015152/189/ci/CA120423/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 was tested in SGCA-null mice by transduction with h-Alpha-SG-R98H in one hind-limb. The humanized limb presented signs of dystrophy in skeletal muscle and extreme reduction of alpha-sarcoglycan via immunohistochemistry and western blot (PS3_Moderate; PMID: 34505136). \n\n-0.7 in WashU assay of membrane localization, -1.6 in Lek/Yale assay", "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": "CA120423/MONDO:0015152/189/ci/CA120423/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1825/1827", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/1/1826", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1825", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/MONDO:0015152/189/el/0/1651", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA120423/MONDO:0015152/189/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": "2026/5/7", "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/CA120423/MONDO:0015152/189/el/0/1651/1653", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA120423/MONDO:0015152/189/ci/CA120423/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 (PMID: 32528171, 30564623, 29382405, 12746421, 36575883; Newcastle University internal data communication). Of those individuals, three were presumed compound heterozygous (phase unconfirmed) for the variant and a pathogenic variant (c.229C>T p.(Arg77Cys), 0.5 pts, Newcastle University internal data communication; c.307A>G p.(Ile103Val), 0.5 pts, PMID: 30564623, LOVD Individual #00219726; c.850C>T p.(Arg284Cys), 0.5 pts, 29382405). Three unrelated patients were homozygous for the variant without reported consanguinity (1.0 pts, PMID: 32528171, 36575883) (PM3_Strong).\n\nc.307A>G p.(Ile103Val), c.229C>T p.(Arg77Cys) are all independently P\nco-occurrence checked", "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": "CA120423/MONDO:0015152/189/ci/CA120423/MONDO:0015152/189.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1651/1653", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/1/1652", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189/0/1651", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA120423/MONDO:0015152/189", "metadata": { "created": "2026-05-07T16:14:53.033Z", "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 16:14:52 -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": "a77a5d53-75ac-4487-aebe-2d62b25b9cf8", "variant": { "@id": "https://reg.genome.network/allele/CA120423", "id": "CAR:CA120423", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000023.4:c.293G>A" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000023.4(SGCA):c.293G>A (p.Arg98His)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-18T11:48:03.525Z" } }, "status": { "code": 200, "name": "OK" } }