ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.1181G>C (p.Gly394Ala) (rs756966358)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693450 SCV000821321 uncertain significance Bethlem myopathy 1 2019-03-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 394 of the COL6A2 protein (p.Gly394Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs756966358, ExAC 0.002%). This variant has not been reported in the literature in individuals with COL6A2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Gly394Glu) in affected individuals suggests that this may be a clinically significant residue (PMID: 20976770, 24038877). 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 COL6A2, missense variants at these glycine residues are significantly enriched in individuals with 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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