The NM_000070.3: c.327_328dup p.(Arg110ProfsTer18) variant is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/24, leading to nonsense-mediated decay in a gene in which loss of function is an established disease mechanism (PVS1). This variant has been identified in at least two patients with features consistent with LGMD (PMID: 30564623, 1805549; LOVD CAPN3_000440), including in unconfirmed phase with a pathogenic variant (c.1993-1G>A, 0.5 pts, PMID: 30564623, LOVD Individual #00220608) (PM3_Supporting). At least one individual with this variant and a second presumed diagnostic CAPN3 variant displayed progressive limb girdle muscle weakness as well as absent CAPN3 expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 18055493, LOVD Individual #00214565; PP4_Strong). The upper bound of the 95% confidence interval of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000076118 (74/1179616 European (non-Finnish) alleles), which is less than the VCEP threshold of 0.0001 (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 Limb Girdle Muscular Dystrophy Expert Panel (specification version 2.0.0; 03/12/2026): PVS1, PM3_Supporting, PP4_Strong, PM2_Supporting.