ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6220G>A (p.Gly2074Ser) (rs886044252)

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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 RCV000356761 SCV000344165 pathogenic not provided 2018-07-03 criteria provided, single submitter clinical testing
Invitae RCV000546975 SCV000657370 pathogenic Bethlem myopathy 1 2018-05-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2074 of the COL6A3 protein (p.Gly2074Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a COL6A3-related disease. ClinVar contains an entry for this variant (Variation ID: 289755). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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). Different missense substitution at this codon (p.Gly2074Asp, p.Gly2074Cys) have been determined to be pathogenic (PMID: 18825676, 20976770, 24038877). This suggests that the glycine residue is critical for COL6A3 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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