CAPN3 p.Glu716Asp

The NM_000070.3: c.2148G>T variant in CAPN3 is a missense variant predicted to cause the substitution of glutamic acid to aspartic acid at codon 716, p.(Glu716Asp). This variant has been reported in at least five individuals with features consistent with LGMD (PMID: 15689361, 32994280, 37526466; LOVD CAPN3_000296), including in a homozygous state in one patient without reported familial consanguinity (0.5 pts; PMID: 15689361, LOVD Individual #00311346), confirmed in trans with a likely pathogenic or pathogenic variant (c.1401_1403del p.(Glu467del), 1.0 pt, PMID: 37526466), and in unknown phase with a pathogenic variant (c.967G>T p.(Glu323Ter), 0.5 pts, PMID: 15689361) (PM3_Strong). At least one patient with this variant and a second presumed diagnostic variant in CAPN3 had both a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 15689361; PP4_Strong). The filtering allele frequency for this variant is 0.000008232 (the upper threshold of the 95% CI of 4/11112002 European (non-Finnish) exome chromosomes in gnomAD v4.1.0), which is less than the LGMD VCEP threshold (0.0001), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.84, evidence which correlates with impact to CAPN3 function (PP3). 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; 06/25/2025): PM3_Strong, PP4_Strong, PM2_Supporting, PP3.