ClinVar Miner

Submissions for variant NM_000070.2(CAPN3):c.1319G>A (rs376107921)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201096 SCV000255649 pathogenic Limb-girdle muscular dystrophy, type 2A 2013-05-15 criteria provided, single submitter clinical testing
Counsyl RCV000201096 SCV000791421 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2017-05-10 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000520664 SCV000331221 pathogenic not provided 2018-06-05 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762949 SCV000893373 pathogenic Limb-girdle muscular dystrophy, type 2A; MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL DOMINANT 4 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000520664 SCV000616670 pathogenic not provided 2017-05-08 criteria provided, single submitter clinical testing The R440Q variant in the CAPN3 gene has been reported previously in multiple individuals with limb-girdle muscular dystrophy (LGMD) who harbor an additional CAPN3 variant, and had decreased or absent calpain-3 protein on western blot analysis (Groen et al., 2007; Fanin et al., 2009; Sacconi et al., 2012). This variant is observed in 7/30,490 alleles (0.023%) from individuals of South Asian background in large population cohorts (Lek et al., 2016). The R440Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. A different missense variant at the same position (R440W) has been previously reported in association with LGMD (Richard et al., 1997). Additionally, missense variants in nearby residues (E435K, R437C, R437G, G441D, and G445R) have been reported in the Human Gene Mutation Database in association with LGMD (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R440Q as a pathogenic variant.
Invitae RCV000201096 SCV000645468 pathogenic Limb-girdle muscular dystrophy, type 2A 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 440 of the CAPN3 protein (p.Arg440Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs376107921, ExAC 0.04%). This variant has been reported in several individuals affected with limb-girdle muscular dystrophy type 2A (PMID: 19048948, 15221789, 21984748, 20694146, 18055493, 25326637). ClinVar contains an entry for this variant (Variation ID: 217147). Experimental studies have shown that this missense change results in reduced CAPN3 protein expression (PMID: 19048948, 15221789, 20694146, 18055493). For these reasons, this variant has been classified as Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.