Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000412799 | SCV000338311 | likely pathogenic | not provided | 2018-03-05 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000412799 | SCV000491159 | pathogenic | not provided | 2017-05-31 | criteria provided, single submitter | clinical testing | The E716D missense variant has been reported previously in a patient with LGMD2A who also harbored a second CAPN3 variant; however phase was undetermined (Saenz et al., 2005). Functional studies demonstrate a complete loss of the CAPN3 protein in this patient (Saenz et al., 2005). The E716D variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E716D variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. Additionally, a missense variant in a nearby residue (L712F) has been reported in the Human Gene Mutation Database in association with LGMD (Stenson et al., 2014). Therefore, we interpret E716D as a pathogenic variant. |
| Invitae | RCV000644995 | SCV000766732 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2023-10-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 716 of the CAPN3 protein (p.Glu716Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 15689361; Invitae). 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: 285340). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Counsyl | RCV000644995 | SCV000800734 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2017-10-07 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000412799 | SCV002025068 | likely pathogenic | not provided | 2019-01-15 | criteria provided, single submitter | clinical testing | |
| Laboratory of Medical Genetics, |
RCV000644995 | SCV002577415 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2A | 2022-07-14 | criteria provided, single submitter | clinical testing | PM2, PM3, PP2, PP3, PP5 |
| Baylor Genetics | RCV003475907 | SCV004211495 | pathogenic | Muscular dystrophy, limb-girdle, autosomal dominant 4 | 2023-10-31 | criteria provided, single submitter | clinical testing |