This variant has been reported in at least six patients with clinical features consistent with LGMD2A (PMID: 15689361, 26501342, 25135358, 17702496, 17236769, 15733273), including in unconfirmed phase with a pathogenic variant in at least three patients (c.2362-2363delinsTCATCT, 0.5 pts, PMID: 15689361; c.550del, 0.5 pts x2, PMID: 17702496, 15733273) (PM3). Saenz: 0.5 pts, c.2362-2363delinsTCATCT unknown phase LGMD VCEP curation and scoring of cases entered by the Broad: PMID: 26501342 Chen et al. (2015) Patient with LGMD, reported compound heterozygote with genotype c.1322delG and c.1465C>T (p.Arg489Trp), which we haven't curated yet but is pathogenic in ClinVar (ClinVar Variation ID: 217150), PMID 25135358 Stehlíková et al. (2014) Patient 59: in unknown phase with c.2114A>G p.(Asp705Gly) , not yet curated PMID 17702496 Hanisch et al. (2007) 4. Patient 10 (7 y o), myalgia, hyperCKemia (5,365), mild myopathic inflammatory reaction on muscle biopsy, signs of myopathy on EMG. reduced 90 kDa band, absent 60 kDa band, normal 30 kDa band on WB. in unconfirmed phase with c.550delA (approved at P, 0.5 pts) German PMID: 17236769 Milic et al. Patient D25 with LGMD. Reported compound heterozygote with c.1099G>A (p.Gly367Ser) but methodology for phasing not confirmed, not in VCI (0.0 pts). Normal autolytic and proteolytic calapain-3 activity in vitro and normal expression on WB of muscle biopsy. PMID: 15733273 Todorova et al. (2005) Patient 3, unconfirmed phase with c.550delA (Pathogenic, ClinVar Variation ID: 17621) (0.5 pts). absent calpain-3 on WB. Onset at age 3 with difficulty with stairs. calf hypertrophy and scapula alata. No hip adductor, hip abductor, abdominal muscle weakness at age 11.

This variant has been identified with a second presumed diagnostic CAPN3 variant in at least one individual with a clinical diagnosis of LGMD and absent calpain-3 protein expression in skeletal muscle, which is highly specific for CAPN3-related LGMD (PMID: 15733273; PP4_Strong). PMID: 15733273 Todorova et al. (2005) Patient 3, unconfirmed phase with c.550delA (Pathogenic, ClinVar Variation ID: 17621) (0.5 pts). absent calpain-3 on WB. Onset at age 3 with difficulty with stairs. calf hypertrophy and scapula alata. No hip adductor, hip abductor, abdominal muscle weakness reported at age 11 but phenotype considered clinically consistent with a diagnosis of LGMD.

The upper bound of the 95% confidence interval (95% CI) of the Grpmax variant allele frequency in gnomAD v4.1.0 is 0.000008921 (5/1178404 European (non-Finnish) chromosomes), which is less than the ClinGen LGMD VCEP threshold (≤0.0001) (PM2_Supporting).

The NM_000070.3: c.1322del p.(Gly441ValfsTer22) variant in CAPN3 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/24, leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism (PVS1).