ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.1666G>A (p.Gly556Arg) (rs886043521)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000316226 SCV000340529 likely pathogenic not provided 2016-03-23 criteria provided, single submitter clinical testing
Invitae RCV000260990 SCV000835703 uncertain significance Bethlem myopathy 1 2018-04-09 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 556 of the COL6A1 protein (p.Gly556Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL6A1-related disease. ClinVar contains an entry for this variant (Variation ID: 286928). 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). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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