CAPN3 p.Arg769Gln

The NM_000070.3: c.2306G>A variant in CAPN3 is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid position 769, p.(Arg769Gln). The variant has been detected in a homozygous state in more than 30 individuals with LGMD (1.0 pt, PMID: 14645990, 12461690, 7720071, 23553538, LOVD CAPN3_000013; PM3). It was also observed to segregate with autosomal recessive LGMD in eight affected family members from two families and was found in a homozygous state in all affected patients in 10 families from the Plain community in northern Indiana (PMID: 12461690, 7720071; PP1_Strong). At least one patient homozygous for this variant showed progressive limb girdle muscle weakness and absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 14645990; PP4 (capped with PP1_Strong)). The filtering allele frequency of this variant is 0.000089887 in gnomAD v4.1.0 exomes (the upper threshold of the 95% CI of 3/86258 South Asian chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting). The computational predictor REVEL gives a score of 0.947, which is above the threshold of 0.70 (PP3). SpliceAI predicts the possible loss of an alternate splice donor site due to this variant, with a score of 0.49. However, a minigene assay for this variant demonstrated a largely preserved expression of transcripts with normal splicing (PMID: 32668095). In summary, this variant is classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 04/22/2025). While the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP, result in 9 Bayesian points (PM3, PP1_Strong, PP4, PM2_Supporting, PP3), a classification of Pathogenic was awarded given the strength of the available evidence and the impact of scoring caps on homozygous case data and locus-specific segregation and phenotype evidence.