CAPN3 p.Asp419Glu

The NM_000070.3: c.1257T>G variant in CAPN3 is a missense variant predicted to cause substitution of aspartic acid by glutamic acid at amino acid 419 (p.Asp419Glu). This variant has been detected in at least ten unrelated individuals with LGMD (PMID: 18055493, 25079074, 30564623; LOVD CAPN3_000280; ClinVar SCV000953543.3 internal data communication, ClinVar SCV002025057.3 internal data communication, ClinVar SCV001879783.1 internal data communication), including in unknown phase with a pathogenic variant in six cases (c.550delA p.(Thr184ArgfsTer36), 1.0 pt, PMID: 18055493, SCV002025057.3; c.1469G>A p.(Arg490Gln), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1027G>T p.(Glu343Ter), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.1838del p.(Lys613ArgfsTer49), 0.5 pts, ClinVar SCV000953543.3 internal data communication; c.643_663del p.(Ser215_Gly221del), 0.5 pts, ClinVar SCV001879783.1 internal data communication) (PM3_Strong). In four individuals, a second variant in CAPN3 was not identified. At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PMID: 18055493) (PP4). The filtering allele frequency of this variant is 0.00006819 (the upper threshold of the 95% CI of 3/113704 European (non-Finnish) exome alleles) by gnomAD v2.1.1, which is less than the LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.83, which exceeds the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 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 1.0.0; 01/09/2025): PM3_Strong, PP4, PM2_Supporting, PP3.