ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6230G>T (p.Gly2077Val) (rs1553553646)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000529470 SCV000657372 pathogenic Bethlem myopathy 1 2018-02-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2077 of the COL6A3 protein (p.Gly2077Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with muscle weakness (Invitae). A different missense substitution at this codon (p.Gly2077Arg) has been reported in two individuals affected with collagen VI myopathy (PMID: 24038877). Glycine residues within the triple helix region are crucial to maintain fibrillar collagens structure and stability (PMID: 7695699, 19344236). In the case of COL6A3, missense substitutions that affect glycine residues within the triplex helix domain have been reported in many patients affected with collagen VI myopathy (PMID: 24038877). 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. For these reasons, this variant has been classified as Pathogenic.

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