CAPN3 p.Ser443Pro

The NM_000070.3: c.1327T>C variant in CAPN3 is a missense variant predicted to cause substitution of serine with proline at amino acid position 443, p.(Ser443Pro). This variant has been detected in at least six unrelated individuals with LGMD, where it was identified in unconfirmed phase with two unique pathogenic variants (c.1505T>C p.(Thr501Ile), 0.5 pts x3, PMID: 35135626, 26810512, 39258114; c.1746-20C>G, 0.5 pts x3, GRASP-LGMD Consortium, ClinVar SCV000960844.6 internal data communication) (PM3_Strong). At least one patient with this variant and a second CAPN3 variant displayed progressive limb girdle muscle weakness and significantly reduced calpain-3 protein expression, which is specific for CAPN3-related LGMD (PMID: 35135626, 26810512; PP4_Moderate). The Grpmax variant allele frequency in gnomAD v.4.1.1 is 0.000001698 in the European (non-Finnish) population (2/1177684 chromosomes) (PM2_Supporting). The computational predictor REVEL gives a score of 0.896, which is above the LGMD 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 (specifications v2.0.0; 04/29/2026): PM3_Strong, PP4_Moderate, PM2_Supporting, PP3.