CAPN3 p.Arg490Gln

The NM_000070.3: c.1469G>A variant in CAPN3 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 490 (p.Arg440Gln). This variant has been detected in at least 16 individuals with limb girdle muscular dystrophy (PMID: 26404900, 18055493, 10330340, 22378277, 22443334, 18854869), including in a homozygous state in at least four cases (1.0 pt; PMID: 18055493, 10330340, 22443334) and confirmed in trans with a pathogenic variant in three cases (c.550del p.(Thr184ArgfsTer36), 3.0 pts, PMID: 26404900, 18854869, 22378277) (PM3_Very Strong). At least one patient with this variant displayed progressive limb girdle muscle weakness or a clinical suspicion of LGMD (PP4). The highest population minor allele frequency of this variant is 0.0001846 (3/16248 exome alleles) in the African/African American population in gnomAD v2.1.1, which is greater than the LGMD VCEP threshold (<0.0001) for PM2_Supporting (criterion not met). The computational predictor REVEL gives a score of 0.94, which is above the VCEP threshold of 0.70, evidence that correlates with impact to CAPN3 function (PP3). Another missense variant at the same codon, c.1468C>T p.(Arg490Trp), has been classified as pathogenic for autosomal recessive limb girdle muscular dystrophy by the 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 1.0.0; 01/09/2025): PM3_Very Strong, PP4, PP3, PM5.