CAPN3 p.Asp764fs

The NM_000070.3: c.2290del p.(Asp764ThrfsTer12) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 22/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been reported in at least three patients with features consistent with LGMD, including in a homozygous state in one patient without reported familial consanguinity (0.5 pts, PMID: 31671740, LOVD Individual #00416186) and confirmed in trans with a pathogenic variant in two patients (c.2362_2363delinsTCATCT p.(Arg788SerfsTer14), 1.0 pt x2, LOVD Individual #00214755; ClinVar SCV002227607.3 personal data communication) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in CAPN3 had a clinical diagnosis of LGMD (LOVD Individual #00214755; PP4). The highest minor allele frequency of this variant is 0.00004472 (2/44722 exome chromosomes) for the Admixed American population in gnomAD v4.1.0, which is lower than the LGMD VCEP threshold (<0.0001) for PM2_Supporting, meeting this criterion (PM2_Supporting). 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; 05/03/2025): PVS1, PM3_Strong, PP4, PM2_Supporting.