Total submissions: 8
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000490012 | SCV000334209 | pathogenic | not provided | 2018-05-22 | criteria provided, single submitter | clinical testing | |
| Gene |
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. |
| Invitae | 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 - |
RCV001814143 | SCV001755517 | pathogenic | Abnormality of the musculature | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000490012 | SCV002025059 | likely pathogenic | not provided | 2020-01-06 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
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 | 2023-09-28 | 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 |