ClinVar Miner

Submissions for variant NM_000070.3(CAPN3):c.590G>A (p.Arg197His)

dbSNP: rs768426565
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000387421 SCV000390999 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2018-04-30 criteria provided, single submitter clinical testing The CAPN3 c.590G>A (p.Arg197His) missense variant has been reported in at least two studies in which it is found in a compound heterozygous state with a second missense and a deletion variant in at least two patients with calpainopathy (Piluso et al. 2005; Fanin et al. 2009). The p.Arg197His variant was absent from 300 controls and is reported at a frequency of 0.000371 in the East Asian population of the Genome Aggregation Database. Functional studies based on Western blotting demonstrated significantly reduced expression of calpain 3 protein in muscle biopsies of both patients carrying the variant as compared to controls (Fanin et al. 2009). The evidence for this variant is limited. The p.Arg197His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Counsyl RCV000387421 SCV000788718 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2017-01-17 criteria provided, single submitter clinical testing
Invitae RCV000387421 SCV000821569 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2A 2022-05-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 197 of the CAPN3 protein (p.Arg197His). This variant is present in population databases (rs768426565, gnomAD 0.04%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 16141003, 18854869). ClinVar contains an entry for this variant (Variation ID: 315892). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Revvity Omics, Revvity Omics RCV003144203 SCV003830566 uncertain significance not provided 2021-05-25 criteria provided, single submitter clinical testing
GeneDx RCV003144203 SCV004031016 uncertain significance not provided 2023-08-23 criteria provided, single submitter clinical testing Identified with a second CAPN3 variant in patients with limb girdle muscular dystrophies, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Piluso et al., 2005; Fanin et al., 2009); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15221789, 20460380, 18854869, 34426522, 16141003)
Baylor Genetics RCV003475931 SCV004211515 likely pathogenic Muscular dystrophy, limb-girdle, autosomal dominant 4 2023-10-22 criteria provided, single submitter clinical testing

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