{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/c3a6675d-60b5-47c8-9a29-98000a3aa6c2/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/CA347216867/MONDO:0015152/180/el/0/1738", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/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": "2025/9/5", "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/CA347216867/MONDO:0015152/180/el/0/1738/1740", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347216867/MONDO:0015152/180/ci/CA347216867/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 patient had a clinical diagnosis of LGMD and absent dysferlin protein expression by immunohistochemistry and western blot of skeletal muscle (PMID: 36983702, 33610434; PP4_Strong). ", "contributionDate": { "date": "2025/9/5", "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": "CA347216867/MONDO:0015152/180/ci/CA347216867/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1738/1740", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/1/1739", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1738", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/MONDO:0015152/180/el/0/1765", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/MONDO:0015152/180/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": "2025/9/5", "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/CA347216867/MONDO:0015152/180/el/0/1765/1767", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347216867/MONDO:0015152/180/ci/CA347216867/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": "Another nucleotide change affecting the same splice donor site and with the same predicted and experimentally demonstrated splice effect, NM_003494.4: c.3031+2T>C, is classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (PS1_Supporting).\n\nCurated variant: \nSpliceAI 0.9 for donor loss (p-score 0.09) and 0.44 (p-score 0.46) for gain of alternative donor into the intron at +59\nGENEie: 99.9% probability splice-altering\n3 NIF stars: mean NIF impact -98% but no NIF 0 window\n3 similar impact variants: c.3085+1G>T, c.3085+1G>A, c.3085+2T>C\nSpliceVAULT top 3 are all out of frame: skipping of exon 28 and use of 2 cryptic donors\nRNAseq data showed two different splice effects: 1) inclusion of the entire DYSF intron 28 which results in a frameshift and the presence of a premature stop codon 120bp into the inserted intron, p.Gly1011Argfs; 2) complete skipping of exon 28, r.2926_3031del, resulting in a frameshift and premature truncation, p.Asn976AlafsX46. NMD expected for both of these events. \n\nComparison variant c.3031+2T>C\nSpliceAI 0.92 for donor loss (alt 0.07) and 0.39 (alt 0.42) for gain of alternative donor into the intron at +59\nGENEie: Uncertain (another variant causing the same sequence change in another gene called LB but without evidence)\n2 NIF stars: mean NIF impact -96% but no NIF 0 window\n2 similar impact variants: c.3085+1G>T, c.3085+1G>A. Note that the curated variant is not yet in ClinVar and so I believe was not eligible as a similar impact variant.\nSpliceVAULT top 3 are all out of frame: skipping of exon 28 and use of 2 cryptic donors\nshown by RNAseq to cause skipping of exon 28, resulting in a frameshift and premature truncation\n\nSimilar SpliceAI scores, same experimentally demonstrated consequence of exon skipping resulting in NMD but curated variant had additional effect of intron retention (also resulting in NMD so same functional consequence). Comparison variant located within same splice region and at +/-1,2 dinucleotide position and classified as P (PVS1_RNA, PM3, PP4, PP1_Strong, PM2_Supporting). \nif computational code applicable to curated variant is PVS1_RNA, PS1_Supporting \nif computational code applicable to curated variant is PVS1_Strong, _Moderate, or _Supporting _RNA, PS1 \nPer VCEP discussion, could probably apply given same functional consequence of splice effects, but P classification already reached. \n\npolyA (adenylated transcripts only) vs ribosomal depleted total RNA", "contributionDate": { "date": "2025/9/5", "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": "CA347216867/MONDO:0015152/180/ci/CA347216867/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1765/1767", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/1/1766", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1765", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/MONDO:0015152/180/el/0/1762", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/MONDO:0015152/180/ei/1/1763", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/9/5", "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/CA347216867/MONDO:0015152/180/el/0/1762/1764", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347216867/MONDO:0015152/180/ci/CA347216867/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.3031G>C variant in DYSF, which is also known as NM_001130987.2: c.3085G>C p.(Gly1029Arg), is a missense variant predicted to cause substitution of glycine by arginine at amino acid 1011, p.(Gly1011Arg). This variant affects the last nucleotide of exon 28, and RNAseq analysis has demonstrated two different splice effects: inclusion of intron 28 and skipping of exon 28. Both of these events result in a frameshift and premature truncation for which nonsense mediated decay is expected; however, the possibility of retention of some degree of constitutive splicing was not ruled out (PVS1_Strong_RNA). \n\nSpliceAI:\n0.9 for loss of annotated donor (alt 0.09)\n0.44 for gain of alternative donor in the intron at +59 (alt 0.46)\n\nGENEie:\n99.9% probability splice-altering\n3 NIF stars: mean NIF impact -98% but no NIF 0 window\n\nSpliceVAULT top 3 are all out of frame: skipping of exon 28 (3,694 samples) and use of 2 cryptic donors: +59 (95 samples), +158 (34 samples)\n\nRNAseq:\ninclusion of entire intron 28, resulting in p.Gly1011Argfs (new stop codon 120 bp into the inserted intron 28)\nskipping of exon 28, resulting in p.Asn976AlafsX46\nquantification not done: 40% intron retention, 8% exon skipping, 52% ref\n\nDowngrading to PVS1_Strong_RNA would not change P classification", "contributionDate": { "date": "2025/9/5", "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": "CA347216867/MONDO:0015152/180/ci/CA347216867/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1762/1764", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/1/1763", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1762", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/MONDO:0015152/180/el/0/1609", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/MONDO:0015152/180/ei/1/1610", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50061_EP173626590511418", "id": "CG-PCER-AGENT:CG_50061_EP173626590511418", "type": "Agent" }, "contributionDate": { "date": "2025/9/5", "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/CA347216867/MONDO:0015152/180/el/0/1609/1611", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347216867/MONDO:0015152/180/ci/CA347216867/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 observed in unknown phase with a pathogenic variant in one patient with features consistent with LGMD (NM_003494.4: c.855+1del, 0.5 pts, PMID: 36983702; PM3_Supporting). \n\ncannot check co-occurrence data", "contributionDate": { "date": "2025/9/5", "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": "CA347216867/MONDO:0015152/180/ci/CA347216867/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1609/1611", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/1/1610", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1609", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/MONDO:0015152/180/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA347216867/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": "2025/9/5", "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/CA347216867/MONDO:0015152/180/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA347216867/MONDO:0015152/180/ci/CA347216867/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 is absent from gnomAD v4.1.0 (PM2_Supporting). ", "contributionDate": { "date": "2025/9/5", "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": "CA347216867/MONDO:0015152/180/ci/CA347216867/MONDO:0015152/180.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA347216867/MONDO:0015152/180", "metadata": { "created": "2025-09-05T14:20:47.428Z", "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, 05 Sep 2025 14:20:47 -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": "c3a6675d-60b5-47c8-9a29-98000a3aa6c2", "variant": { "@id": "https://reg.genome.network/allele/CA347216867", "id": "CAR:CA347216867", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_003494.4:c.3031G>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_003494.4:c.3031G>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-11-04T21:15:41.473Z" } }, "status": { "code": 200, "name": "OK" } }