ClinVar Miner

Submissions for variant NM_001849.3(COL6A2):c.1288G>A (p.Gly430Ser) (rs765430501)

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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 RCV000490233 SCV000344181 uncertain significance not provided 2018-06-18 criteria provided, single submitter clinical testing
GeneDx RCV000490233 SCV000577647 likely pathogenic not provided 2015-08-13 criteria provided, single submitter clinical testing The G430S variant in the COL6A2 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The G430S variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G430S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G430S variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded.
Invitae RCV000653582 SCV000775464 uncertain significance Bethlem myopathy 1 2017-12-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 430 of the COL6A2 protein (p.Gly430Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs765430501, ExAC 0.8%). This variant has not been reported in the literature in individuals with COL6A2-related disease. ClinVar contains an entry for this variant (Variation ID: 289769). 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). 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 C0"). 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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