Submissions for variant NM_000070.3(CAPN3):c.865C>T (p.Arg289Trp)

gnomAD frequency: 0.00004  dbSNP: rs528417986

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000490012	SCV000334209	pathogenic	not provided	2018-05-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000490012	SCV000577116	pathogenic	not provided	2017-04-11	criteria provided, single submitter	clinical testing	The R289W variant in the CAPN3 gene has been reported previously in association with limb-girdle muscular dystrophy type 2A (Milic et al., 2007; Duno et al., 2008). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R289W 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 vitro studies on muscle from an individual who harbored both the R289W variant and a loss of function variant demonstrated absence of calpain-3 protein and absence of enzymatic activity (Milic et al., 2007). We interpret R289W as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000340129	SCV000645517	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 289 of the CAPN3 protein (p.Arg289Trp). This variant is present in population databases (rs528417986, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 17236769, 18337726, 25135358). 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: 282646). 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 expected to disrupt CAPN3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814143	SCV001755517	pathogenic	Abnormality of the musculature	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000490012	SCV002025059	likely pathogenic	not provided	2020-01-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271482	SCV002556092	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-06-23	criteria provided, single submitter	clinical testing	Variant summary: CAPN3 c.865C>T (p.Arg289Trp) results in a non-conservative amino acid change located in the Peptidase C2, calpain, catalytic domain (IPR001300) 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 2.4e-05 in 251474 control chromosomes. c.865C>T has been reported in the literature as a compound heterozygous genotype in at-least three individuals with a clinical diagnosis of Limb-Girdle Muscular Dystrophy, Autosomal Recessive (LGMD2A) who have been subsequently included in other studies (example, Milic_2007, Duno_2008, Hauerslev_2012, Stehlikova_2014, Ten Dam_2019, Topf_2020, Barp_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003475896	SCV004211556	likely pathogenic	Muscular dystrophy, limb-girdle, autosomal dominant 4	2024-03-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000340129	SCV000793156	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2A	2017-08-11	no assertion criteria provided	clinical testing