CAPN3 p.Gly367Ser

The NM_000070.3: c.1099G>A variant in CAPN3 is a missense variant expected to result in the substitution of glycine with serine at amino acid 367, p.(Gly367Ser). This variant has been identified in at least 7 patients with features consistent with LGMD (PMID: 15689361, 17236769, 25079074, 32403337, 33250842, 34201303; ClinVar SCV000645461.5 internal data communication), including confirmed in trans with a whole gene deletion in one individual (1.0 pt, ClinVar SCV000645461.5 internal data communication) and in unconfirmed phase with a pathogenic variant in two cases (c.759_761del p.(Lys254del), 0.5 pts, PMID: 15689361; c.1322del p.(Gly441ValfsTer22), 0.5 pts, PMID: 34201303) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 allele displayed progressive limb girdle muscle weakness (PP4). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.0003851 (the upper threshold of the 95% CI of 23/84620 South Asian chromosomes), which is greater than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting not met). The computational predictor REVEL gives a score of 0.955, which is above the LGMD VCEP threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Likely pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 2.0.0; 10/28/2025): PP3, PM3_Strong, PP4.