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

dbSNP: rs768426565

Total submissions: 6

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000387421	SCV000821569	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2A	2024-07-19	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 individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 18854869). ClinVar contains an entry for this variant (Variation ID: 315892). 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%. This variant disrupts the p.Arg197 amino acid residue in CAPN3. Other variant(s) that disrupt this residue have been observed in individuals with CAPN3-related conditions (PMID: 15689361, 16141003, 30564623, 33337384), which suggests that this may be a clinically significant amino acid residue. 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	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	2024-03-28	criteria provided, single submitter	clinical testing