ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.2257G>A (p.Asp753Asn) (rs146923842)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000723527 SCV000331248 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing
Counsyl RCV000410341 SCV000485675 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2016-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000723527 SCV000568287 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CAPN3 gene. The D753N variant was reported previously, without a second identifiable CAPN3 variant, in an individual with LGMD2A who had complete calpain-3 deficiency on Western blot (Fanin et al., 2004). The D753N variant was subsequently reported in the heterozygous and compound heterozygous state in association withLGMD2A; however, parental testing was not completed and functional characterization of the variant was not performed (Piluso et al., 2005; Sáenz et al., 2005; Todorova et al., 2007). The D753N variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, but the 1000 Genomes Project reports D753N was observed in 2/1006 (0.2%) alleles from individuals of European background, in 1/170 (0.6%) alleles from individuals of Peruvian background, and in 1/172 (0.6%) alleles from individuals of Bengali background. The D753N 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 where amino acids with similar properties to Aspartic acid are tolerated across species. Missense variants in nearby residues (R748Q, N749H) have been reported in the Human Gene Mutation Database in association with CAPN3-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000410341 SCV000645492 uncertain significance Limb-girdle muscular dystrophy, type 2A 2019-01-02 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 753 of the CAPN3 protein (p.Asp753Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs146923842, ExAC 0.1%). This variant has been reported in several individuals affected with limb girdle muscular dystrophy (PMID: 16141003, 18854869). Segregation studies have not been reported for this variant. ClinVar contains an entry for this variant (Variation ID: 281081). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Clinical Services Laboratory,Illumina RCV000410341 SCV000915670 likely pathogenic Limb-girdle muscular dystrophy, type 2A 2019-01-09 criteria provided, single submitter clinical testing Across a selection of the available literature, the CAPN3 c.2257G>A (p.Arg753Asn) is identified in six probands described to have limb girdle muscular dystrophy in a heterozygous state and five probands in a compound heterozygous state (Fanin et al. 2004; Piluso et al. 2005; Saenz et al. 2005; Todorova et al. 2007; Fanin et al. 2009). The p.Arg753Asn variant absent from at least 400 controls and is reported at a frequency of 0.00118 in the European (non-Finnish) population of the Exome Aggregation Consortium. Todorova et al. (2007) noted that the variant, when observed in a heterozygous state in probands with limb girdle muscular dystrophy, seemed to confer a later onset and milder phenotype. Based on the evidence, the p.Asp753Asn variant is classified as likely pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

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