The NM_000070.3: c.1981del p.(Ile661Ter) variant in CAPN3, which is also known as p.(Gln660_Ile661insTer), is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 17/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been detected in at least 11 patients with features consistent with LGMD (PMID: 30919934, 37526466, 19556129, 18337726, 18055493; LOVD CAPN3_000104), including confirmed in trans with a pathogenic variant in one individual (c.550del p.(Thr184Argfs36), 1.0 pt, PMID: 37526466), in unknown phase with a pathogenic variant in another individual (c.1838del p.(Lys613ArgfsTer49), 0.5 pts, PMID: 18055493), and in a homozygous state in an individual without reported familial consanguinity (0.5 pts, PMID: 18055493) (PM3_Strong). This variant has also been reported to co-segregate with autosomal recessive LGMD in four affected family members from two families (PMID: 30919934; PP1_Strong). In addition, at least one patient with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness and severely reduced or absent expression of calpain-3 protein in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 18337726, 19556129) (PP4, capped with PP1_Strong). The filtering allele frequency of this variant is 0.000061919 (the upper threshold of the 95% CI of 55/1111948 European (non-Finnish) exome chromosomes) in gnomAD v4.1.0, which is less than the ClinGen LGMD VCEP threshold (≤0.0001), 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; 05/14/2025): PVS1, PM3_Strong, PP1_Strong, PP4, PM2_Supporting.