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      "label": "ClinGen Limb Girdle Muscular Dystrophy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CAPN3 Version 2.0.0",
      "type": "VariantPathogenicityInterpretationGuideline",
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                        "comments": " At least one individual with this variant displayed progressive limb girdle muscle weakness or had a clinical suspicion of LGMD.  PMID: 37974208\n",
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                        "comments": "1. signs of myopathy or dystrophy are present in skeletal muscle \n2. an effect on gene or protein function is demonstrated (e.g., decreased protein expression, impaired membrane localization, or other functional abnormality)\n\nThese two articles discusses the R769Q mutation in cell cultures, but does not present new experimental data from human muscle tissue specifically for this variant. However, it summarizes prior findings (including their own earlier studies) indicating that R769Q causes hyper-rapid autolysis, leading to absent CAPN3 protein in Western blot from muscle. PMID 26363099, 9642272 (Ono 1998, 2016)\n\nCOS7 cells – a monkey kidney fibroblast cell line.\nTransfected with human p94 (CAPN3) wild-type or mutant cDNA.\nWestern blot performed on: Total COS7 cell lysates (not muscle).\n\nantibodies used:\nAnti-IS2: Targets the IS2 domain unique to p94 (CAPN3).\nAnti-fodrin cleavage product: To detect 150-kDa fragment indicating proteolytic activity.\n\nKey observations:\nWT CAPN3 showed a 55-kDa autolytic fragment.\nR769Q was not detected, unless co-expressed with the C129S inactive mutant (indicating hyper-rapid autolysis).\nAll mutants (including R769Q) failed to generate the 150-kDa fodrin cleavage fragment → no substrate proteolysis.",
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                        "comments": "The variant has been detected in at least 7 unrelated patients with features consistent with LGMD (PMID: 25987458, 32994280, 37974208, 16607617; ClinVar SCV000948242.5 internal data communication), including in a homozygous state without reported consanguinity in one case (0.5 pts, PMID: 37974208) and confirmed in trans with a pathogenic variant in one case (c.2120A>G (p.Asp707Gly), 1.0 pt, PMID: 37974208) (PM3). \n\nPM3_Very Strong (4 pts) needed to go from LP to P; currently at 1.5 PM3 pts so need 2.5\nunscored cases:\nc.2050+1G>A: unknown phase, 0.5 if P; exon 18 skipping would be out of frame, cryptic use would be out of frame; expect PVS1; preliminary curation suggests P (in VCI)\nc.1343G>T p.(Arg448Leu): unknown phase, 0.5 if P; ; preliminary curation suggests LP (in VCI)\nc.802-9G>A: unknown phase, 0.5 if P; PP3 applies; preliminary curation suggests P (in VCI)\nc.1720T>G p.(Phe574Val): in trans, 1.0 if LP; preliminary curation suggests VUS since only a single patient (in VCI)\nno additional curation pursued at this time\n\n \n",
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                        "comments": "Another missense change at the same position, c.2306G>A p.(Arg769Gln), has been classified as pathogenic for autosomal recessive LGMD by the LGMD VCEP (PM5). \n\nrequirements:\nThe Revel score for curated variant is >0.7\nNot located near an exon-intron boundary.\nThe highest unmasked SpliceAI score for the curated variant is 0.01 (<0.5 threshold). (The masked 0.51 score is for weakening a cryptic donor, which we consider unlikely to be clinically significant.)\nThe highest unmasked SpliceAI score for the comparison variant is 0.02 (<0.5 threshold). (The masked 0.49 score is for weakening a cryptic donor, which we consider unlikely to be clinically significant.)\nThe comparison variant has been approved at Pathogenic independent of the classification of this variant. \n                       delta                                      Ref                  Alt\nAcceptor Loss\t0.05\t        -131 bp\t             0.58\t             0.53\nDonor Loss\t0.51\t         0 bp\t              0.54\t             0.04\nAcceptor Gain\t0.01\t         9 bp\t              0.00\t              0.01\nDonor Gain\t0.00\t         69 bp\t              0.01\t              0.0",
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                        "comments": "The highest population allele frequency of this variant is 0.00001666 in the Admixed American population of gnomAD v4.1.0 (1/60020 chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).\n",
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    "id": "CG-PCER-VARINT:CA392002041/MONDO:0015152/187",
    "metadata": {
      "created": "2026-04-09T23:53:25.070Z",
      "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, 09 Apr 2026 23:48:44 -0000",
      "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)",
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      "@id": "https://loinc.org/LA26332-9",
      "id": "LN:LA26332-9",
      "label": "Likely Pathogenic"
    },
    "type": "VariantPathogenicityInterpretation",
    "uuid": "1370b0a2-bea2-462c-8438-b3b9d0ce5615",
    "variant": {
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      "relatedContextualAllele": [
        {
          "alleleName": [
            {
              "name": "NM_000070.3:c.2306G>C"
            }
          ],
          "preferred": true
        }
      ],
      "relatedIdentifier": [
        {
          "label": "NM_000070.3(CAPN3):c.2306G>C (p.Arg769Pro)"
        }
      ],
      "type": "CAR"
    }
  },
  "metadata": {
    "rendered": {
      "by": "https://erepo.genome.network/evrepo/api/summary/srvc",
      "when": "2026-11-05T03:02:18.309Z"
    }
  },
  "status": {
    "code": 200,
    "name": "OK"
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}