ClinVar Miner

Submissions for variant NM_001848.2(COL6A1):c.1022G>T (p.Gly341Val) (rs121912935)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000521707 SCV000334053 pathogenic not provided 2017-11-14 criteria provided, single submitter clinical testing
GeneDx RCV000521707 SCV000617763 pathogenic not provided 2018-08-06 criteria provided, single submitter clinical testing The G341V pathogenic variant in the COL6A1 gene has been previously reported in multiple unrelated individuals with Bethlem myopathy (Lampe et al., 2005; Lucioli et al., 2005; Deconinck et al., 2014; Ghaoui et al., 2015). Reported individuals did not have a second identifiable COL6A1 pathogenic variant, and G341V was found to be de novo in two cases (Deconinck et al., 2014; Ghaoui et al., 2015). The G341V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs within the Gly-X-Y motif in the triple helical (TH) domain of collagen VI, a region that is well-conserved across species. Additionally, a different missense variant at the same position (G341D) has been previously reported in a family with autosomal dominant Bethlem myopathy (Scacheri et al., 2002). Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae RCV000267474 SCV000656970 pathogenic Bethlem myopathy 1 2019-09-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 341 of the COL6A1 protein (p.Gly341Val). 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 reported to segregate with autosomal dominant Bethlem myopathy in an affected family (PMID: 15955946). It has also been reported in the heterozygous state in multiple individuals affected with Bethlem myopathy (PMID: 25535305, 15689448, 22075033) and has been shown to arise de novo in an individual affected with a limb-girdle muscular dystrophy phenotype (PMID: 26436962) and an individual affected with an intermediate form of COL6A1-myopathy (PMID: 20576434). ClinVar contains an entry for this variant (Variation ID: 282533). 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. 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). A different missense substitution at this codon (p.Gly341Asp) has been determined to be pathogenic (PMID: 11865138, 24038877). This suggests that the glycine residue is critical for COL6A1 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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