ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2243G>A (p.Arg748Gln) (rs587780290)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000116542 SCV000150495 pathogenic Limb-girdle muscular dystrophy, type 2A 2013-11-07 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000116542 SCV000255661 pathogenic Limb-girdle muscular dystrophy, type 2A 2015-02-19 criteria provided, single submitter clinical testing
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000116542 SCV000267239 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2016-03-18 criteria provided, single submitter reference population
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000489478 SCV000331504 pathogenic not provided 2017-11-10 criteria provided, single submitter clinical testing
GeneDx RCV000489478 SCV000577258 pathogenic not provided 2017-04-06 criteria provided, single submitter clinical testing The R748Q variant in the CAPN3 gene has been reported previously in association with limb-girdle muscular dystrophy, type 2A. The affected individuals had onset within the first two decades of life, ranging from 2.5 years to 15 years of age and all had elevated creatine phosphokinase levels (Richards et al., 1997; Fattahi et al., 2017). The R748Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R748Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Functional studies in rat calpain 2 showed that R748Q, using the alternate nomenclature R628Q, reduced initial enzyme activity and catalytic activity, suggesting R748Q in human CAPN3 is damaging (Garnham et al., 2009). We interpret R748Q as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000116542 SCV000611185 pathogenic Limb-girdle muscular dystrophy, type 2A 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000116542 SCV000645491 pathogenic Limb-girdle muscular dystrophy, type 2A 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 748 of the CAPN3 protein (p.Arg748Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous or compound heterozygous state in many individuals affected with limb girdle muscular dystrophy (LGMD) (PMID: 12461690, 9777948, 18854869, 27020652, 18563459, 15689361, 19015733, 22443334, 10330340, 26404900, 9762961, 30028523), and in one affected family it was shown to co-segregate with LGMD (PMID: 9150160). ClinVar contains an entry for this variant (Variation ID: 128570). Experimental studies have shown that this missense substitution reduces CAPN3 catalytic activity as measured by cleavage of an exogenous peptide, which was attributed to an increased rate of autoproteolytic degradation (PMID: 19226146). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000116542 SCV001164496 pathogenic Limb-girdle muscular dystrophy, type 2A 2018-12-03 criteria provided, single submitter research The homozygous p.Arg748Gln variant in CAPN3 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD) This variant has been identified in 0.01455% (5/34372) of Latino chromosomes and 0.004166% (1/24006) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587780290). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. One study that examined a rat model with an analagous protein suggested that this variant affects protein catalytic activity (PMID: 19226146). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enought to determine pathogenicity. The p.Arg748Gln variant in CAPN3 has been reported in many individuals with LGMD in the homozygous and compound heterozygous states in ClinVar and the literature (Variation ID: 128570). This variant segregated with disease in 2 affected relatives from 1 family (PMID: 9150160). There are many reports of individuals with LGMD and this variant (in either the homozygous or compound heterozygous state) in ClinVar and the literature. Animal models in rats have shown that this variant causes LGMD via a deleterious effect on calpain protein catalytic activity (PMID: 19226146). In summary, the p.Arg748Gln variant is pathogenic based off of our findings, multiple reports in ClinVar, and the literature. ACMG/AMP Criteria applied: PM2, PP3, PS3, PP1, PM3_Strong (Richards 2015).
Counsyl RCV000116542 SCV000795867 pathogenic Limb-girdle muscular dystrophy, type 2A 2017-11-21 no assertion criteria provided clinical testing
Natera, Inc. RCV000116542 SCV001456373 pathogenic Limb-girdle muscular dystrophy, type 2A 2020-09-16 no assertion criteria provided clinical testing

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