Submission Details

The relationship between CAPN3 and autosomal recessive limb-girdle muscular dystrophy (LGMDR1 included) has been evaluated using the ClinGen Clinical Validity Framework as of May 2022. The CAPN3 gene is located on chromosome 15q15.q and encodes multiple transcript variants. The longest transcript (NM_000070.3) is 3.5 kb long with 24 exons encoding an 821-amino acid protein. Additional transcripts, derived from alternative splicing and the use of alternative promoter have also been identified. More than 250 pathogenic variants reported in patients with autosomal recessive LGMD are recorded in ClinVar, more than 150 of them being predicted loss of function variants. Limb girdle muscular dystrophy is characterized by progressive weakness in muscles including but not limited to the proximal muscles and affecting the pelvic and shoulder girdle which can lead to difficulty walking or complete loss of ambulation requiring wheelchair use. It is also accompanied by elevated serum creatine kinase and dystrophic and myopathic features. Summary of case level data (12 points): Variants in this gene have been reported in at least 10 probands in 3 publications (PMID: 7720071, 9150160,10330340). Variants in this gene segregated with disease in 24 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease is expected to be biallelic loss of function. Summary of Experimental Data (6 points): This gene-disease relationship is supported by expression studies, biochemical function, protein interaction, animal models, and rescue evidence. Calpain 3 (CAPN3) is a muscle-specific member of the calpain family Ca2+ dependent cysteine proteases and localizes to sarcomere in skeletal muscle (PMID: 9521867, 9777948,15138196, 10229226). Calpain 3 is activated by autolysis. Calpain 3 interacts with multiple skeletal muscle sarcomere and sarcolemma proteins, and many of which are cleaved by active Calpain 3 (PMID: 15138196, 15827562). While the known Calpain 3 substrate list is likely incomplete, Calpine 3 plays important functions in muscle calmodulin pathway, skeletal mTORC1 signaling, mitochondrial biogenesis, and apoptosis (PMID: 10229226, 25389288, 33308300). A number of mouse models by targeted knockout and gene trapping of CAPN3 are reported with phenotype and muscle histological defects similar to human patients with AR-LGMD (PMID: 33308300, 15138196). And rescue in mouse models are also reported (PMID: 16290124, 34514031). In summary, the CAPN3 -autosomal recessive limb-girdle muscular dystrophy gene-disease relationship is definitive. This is demonstrated in both research and clinical diagnostic settings and has been upheld over time.