Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001038863 | SCV001202362 | uncertain significance | Bethlem myopathy 1A | 2020-01-29 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with clinical features of type VI collagenopathy (Invitae). This variant is present in population databases (rs202109302, ExAC 0.01%). This sequence change replaces glycine with arginine at codon 497 of the COL6A1 protein (p.Gly497Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 15689448, 24038877) compared to the general population (ExAC). |
Breakthrough Genomics, |
RCV004693469 | SCV005195202 | uncertain significance | not provided | criteria provided, single submitter | not provided |