ClinVar Miner

Submissions for variant NM_001848.3(COL6A1):c.1255G>A (p.Gly419Ser)

gnomAD frequency: 0.00001  dbSNP: rs745485695
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623439 SCV000740843 uncertain significance Inborn genetic diseases 2015-10-26 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000714618 SCV000845329 uncertain significance Collagen 6-related myopathy 2018-08-07 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000714619 SCV000845330 uncertain significance Bethlem myopathy 1A 2018-08-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000714619 SCV003453873 uncertain significance Bethlem myopathy 1A 2023-08-31 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 520642). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 419 of the COL6A1 protein (p.Gly419Ser). This variant is present in population databases (rs745485695, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant Bethlem myopathy (PMID: 34167565). 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). 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.

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