{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/7e3805af-ba9f-478e-961f-9385ace168f2/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 1.0.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.0.0" }, "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/CA2573135907/MONDO:0015152/180/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2573135907/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": "2025/3/7", "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/CA2573135907/MONDO:0015152/180/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2573135907/MONDO:0015152/180/ci/CA2573135907/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.5181del p.(Glu1727AspfsTer7) variant in DYSF, which is also known as NM_001130987.2: c.5298del (p.Glu1766AspfsTer7), is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 46/55, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). ", "contributionDate": { "date": "2025/3/7", "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": "CA2573135907/MONDO:0015152/180/ci/CA2573135907/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2573135907/MONDO:0015152/180/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2573135907/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": "2025/3/7", "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/CA2573135907/MONDO:0015152/180/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2573135907/MONDO:0015152/180/ci/CA2573135907/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 patient with this variant displayed progressive weakness and severely reduced or absent dysferlin protein expression, which is highly specific for DYSF-associated LGMD (PP4_Strong, PMID: 36983702).\n\nRufibach et al. 2023 (PMID: 36983702)\nJF358: progressive proximal and distal weakness with initial calf hypertrophy that turned into atrophy, muscle biopsy showed dystrophic features, elevated CK. disease range dysferlin by blood monocyte assay. c.1668_1669insGTT p.(Leu556_Leu557insVal) in trans (P by VCEP)", "contributionDate": { "date": "2025/3/7", "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": "CA2573135907/MONDO:0015152/180/ci/CA2573135907/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2573135907/MONDO:0015152/180/el/0/1717", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2573135907/MONDO:0015152/180/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": "2025/3/7", "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/CA2573135907/MONDO:0015152/180/el/0/1717/1719", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2573135907/MONDO:0015152/180/ci/CA2573135907/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 reported in at least two individuals with clinical signs of limb girdle muscular dystrophy, including in a homozygous state (0.5 pts, PMID: 29970176) and confirmed in trans with a likely pathogenic or pathogenic variant (c.1668_1669insGTT p.(Leu556_Leu557insVal), 1.0 pt, PMID: 36983702) (PM3).\n\nNote that the homozygous individual was also homozygous for c.5626G>A p.(Asp1876Asn), which can be classified as Benign based on allele frequency (BA1).\n\nc.1668_1669insGTT can be classified as at least LP without this observation", "contributionDate": { "date": "2025/3/7", "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": "CA2573135907/MONDO:0015152/180/ci/CA2573135907/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1717/1719", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/1/1718", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1717", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2573135907/MONDO:0015152/180/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA2573135907/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": "2025/3/7", "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/CA2573135907/MONDO:0015152/180/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA2573135907/MONDO:0015152/180/ci/CA2573135907/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 highest population minor allele frequency for this variant is 0.0000008474 (1/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0, which is less than the LGMD VCEP threshold (≤0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). ", "contributionDate": { "date": "2025/3/7", "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": "CA2573135907/MONDO:0015152/180/ci/CA2573135907/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA2573135907/MONDO:0015152/180", "metadata": { "created": "2025-03-07T15:00:02.085Z", "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": "Fri, 07 Mar 2025 15:00:01 -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": "7e3805af-ba9f-478e-961f-9385ace168f2", "variant": { "@id": "https://reg.genome.network/allele/CA2573135907", "id": "CAR:CA2573135907", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_001130987.2:c.5298del" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_001130987.2(DYSF):c.5298del (p.Glu1766fs)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-05T10:20:01.496Z" } }, "status": { "code": 200, "name": "OK" } }