ClinVar Miner

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

gnomAD frequency: 0.00018  dbSNP: rs149095128
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000201145 SCV000255664 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2015-08-26 criteria provided, single submitter clinical testing
Eurofins Ntd Llc (ga) RCV000078095 SCV000331474 pathogenic not provided 2016-02-08 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000201145 SCV000391040 pathogenic Autosomal recessive 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 2023-08-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 10330340, 25525159, 11053681, 25135358, 27447704, 22443334, 18055493, 17994539, 18337726, 19556129, 26886200, 30919934, 34405919)
Labcorp Genetics (formerly Invitae), Labcorp RCV000201145 SCV000766716 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 798 of the CAPN3 protein (p.Ala798Glu). This variant is present in population databases (rs149095128, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) (PMID: 17994539, 18055493, 18337726, 19556129, 22443334, 23169433, 25135358; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 92414). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CAPN3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 11053681, 17994539, 18055493, 18337726, 19556129, 22443334). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000078095 SCV002018058 pathogenic not provided 2023-03-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001804832 SCV002051398 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2021-12-28 criteria provided, single submitter clinical testing Variant summary: CAPN3 c.2393C>A (p.Ala798Glu) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251420 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CAPN3 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (8e-05 vs 0.0032), allowing no conclusion about variant significance. c.2393C>A has been reported in the literature in multiple individuals affected with limb girdle muscular dystrophy type 2A (Groen_2007, Guglieri_2008, Duno_2008, Charlton_2009, Hauerslev_2012), including at least one homozygote. These data indicate that the variant is very likely to be associated with disease. Western blot results showed reduced or absent Calpain-3 protein at 94kDa and 30kDa from patients samples who carried this variant (Groen_2007, Guglieri_2008, Duno_2008, Charlton_2009, Hauerslev_2012). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=7) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics, Royal Melbourne Hospital RCV000201145 SCV002503822 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-04-22 criteria provided, single submitter clinical testing This sequence change is predicted to replace alanine with glutamic acid at codon 798 of the CAPN3 protein, p.(Ala798Glu). The alanine residue is highly conserved (100 vertebrates, UCSC), and is located in the Penta E-F hand (PEF) domain (PMID: 26363099). There is a large physicochemical difference between alanine and glutamic acid. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with a recessive condition (rs149095128, 28/282,814 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified homozygous and with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy and segregates with the condition in at least one family (PMID: 18055493, 19556129, 22443334, 25135358, 26886200; LOVD). Absent or reduced calpain 3 protein expression has been identified in the muscle biopsies of multiple cases with the variant (PMID: 18055493, 18337726, 19556129). Multiple lines of computational evidence have conflicting predictions for the missense substitution (2/4 algorithms predict deleterious). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PP1, PP4.
MGZ Medical Genetics Center RCV000201145 SCV002580307 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2021-10-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002504988 SCV002814053 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A; Muscular dystrophy, limb-girdle, autosomal dominant 4 2021-12-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV003474674 SCV004211500 likely pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2024-03-26 criteria provided, single submitter clinical testing
Counsyl RCV000201145 SCV000800759 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-04-24 no assertion criteria provided clinical testing
Natera, Inc. RCV000201145 SCV001456379 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2A 2020-09-16 no assertion criteria provided clinical testing

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