ClinVar Miner

Submissions for variant NM_001848.3(COL6A1):c.895G>A (p.Gly299Arg)

dbSNP: rs2077762322
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001070303 SCV001235525 pathogenic Bethlem myopathy 1A 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 299 of the COL6A1 protein (p.Gly299Arg). For these reasons, this variant has been classified as Pathogenic. 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). 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. ClinVar contains an entry for this variant (Variation ID: 863352). This missense change has been observed in individual(s) with autosomal dominant Ullrich congenital muscular dystrophy (PMID: 20976770). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency).

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