ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2393C>A (p.Ala798Glu) (rs149095128)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201145 SCV000255664 pathogenic Limb-girdle muscular dystrophy, type 2A 2015-08-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078095 SCV000331474 pathogenic not provided 2016-02-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000201145 SCV000391040 pathogenic Limb-girdle muscular dystrophy, type 2A 2017-04-27 criteria provided, single submitter clinical testing Across eight studies, the CAPN3 c.2393C>A (p.Ala798Glu) missense variant was identified in 11 patients with calpainopathy, including two homozygotes, eight compound heterozygotes, and one heterozygote in whom a second variant was not identified (Anderson et al. 2000; Groen et al. 2007; Duno et al. 2008; Charlton R et al. 2009; Hauerslev et al. 2012; Sveen et al. 2013; Stehlíková et al. 2014; Kuhn et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ala798Glu variant is classified as pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx RCV000078095 SCV000617345 pathogenic not provided 2019-01-18 criteria provided, single submitter clinical testing The A798E pathogenic variant in the CAPN3 gene has been previously reported, in both the homozygous and compound heterozygous state, in multiple individuals with limb-girdle muscular dystrophy (Groen et al., 2007; Hauerslev et al., 2012; Stehlikova et al., 2014). The A798E variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A798E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret A798E as a pathogenic variant.
Invitae RCV000201145 SCV000766716 pathogenic Limb-girdle muscular dystrophy, type 2A 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 798 of the CAPN3 protein (p.Ala798Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs149095128, ExAC 0.02%). This variant has been observed as homozygous, or as heterozygous with a second rare CAPN3 variant in several individuals affected with limb-girdle muscular dystrophy type 2A (LGMD2A) (PMID: 18055493, 25135358, 22443334, 19556129, 23169433, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has also been observed as heterozygous in individuals affected with limb-girdle muscular dystrophy in which a second rare variant was not found in CAPN3 (PMID: 17994539, 18337726). ClinVar contains an entry for this variant (Variation ID: 92414). Experimental studies performed on muscle biopsies from individuals affected with LGMD2A who carry this missense change have shown reduced or absent calpain-3 protein (PMID: 18055493, 22443334, 17994539, 19556129, 18337726, 11053681). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000201145 SCV000800759 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2017-04-24 no assertion criteria provided clinical testing
Natera, Inc. RCV000201145 SCV001456379 pathogenic Limb-girdle muscular dystrophy, type 2A 2020-09-16 no assertion criteria provided clinical testing

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.