CAPN3 p.Arg49Cys

The NM_000070.3: c.145C>T variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by cysteine at amino acid position 49, p.(Arg49Cys). This variant has been detected in at least six unrelated individuals with limb girdle muscular dystrophy (PMID: 35198268, 19285864, 19556129, 28403181, 31862442), including in a homozygous state in one individual with known consanguinity (PMID: 19285864, 0.25 pts), confirmed in trans with a pathogenic variant (c.2120A>G p.(Asp707Gly), 1.0 pt, PMID: 28403181), and in unknown phase with a second pathogenic variant in two individuals (c.2242C>T p.(Arg748Ter), 0.5 pt, PMID: 35198268; c.1468C>T p.(Arg490Trp), 0.5 pt, PMID: 19556129) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness as well as absent expression of calpain-3, which is highly specific for CAPN3-related LGMD (PP4_Strong; PMID: 35198268, 19556129). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.1 is 0.0001005 (4/91080 South Asian alleles), which is greater than the VCEP threshold of 0.0001 (PM2_Supporting not met). The computational predictor REVEL gives a score of 0.734, which is above the VCEP threshold of ≥0.70, evidence that correlates with impact to CAPN3 function (PP3). In addition, another missense variant at the same codon, c.146G>A p.(Arg49His), has been classified as pathogenic by the ClinGen LGMD VCEP (PM5). In summary, this variant meets the criteria to be classified as 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; 04/29/2026): PM3_Strong, PP4_Strong, PM5, PP3.