Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481274 | SCV000567159 | pathogenic | not provided | 2015-07-13 | criteria provided, single submitter | clinical testing | The G272D variant in the COL6A1 gene has been reported previously in a mother and son diagnosedwith Bethlem myopathy (Lucioli et al., 2005). The G272D substitution was not observed in approximately6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. The G272D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residuesdiffer in polarity, charge, size and/or other properties. This substitution occurs at a position that isconserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. We interpret G272D as a pathogenic variant. |
| Labcorp Genetics |
RCV002525796 | SCV003444332 | pathogenic | Bethlem myopathy 1A | 2022-02-28 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 419392). 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 COL6A1 protein function. This variant disrupts the triple helix domain of COL6A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL6A1, variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with autosomal dominant COL6A1-related conditions (PMID: 15955946, 29419890, 32528171). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 272 of the COL6A1 protein (p.Gly272Asp). This variant is not present in population databases (gnomAD no frequency). |