ClinVar Miner

Submissions for variant NM_004369.3(COL6A3):c.6158G>T (p.Gly2053Val) (rs886041329)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000334260 SCV000329750 pathogenic not provided 2016-03-21 criteria provided, single submitter clinical testing The G2053V variant in the COL6A3 gene has been reported previously in the heterozygous state, in one individual with a clinical diagnosis of autosomal dominant Bethlem myopathy, characterized by hypotonia, congenital hip dysplasia, motor delays, muscle weakness, finger contractures, distal laxity, moderate respiratory insufficiency and walker-dependent ambulation (Tagliavini et al., 2014). A second, male patient, reported by Butterfield et al., (2013), harbored the heterozygous G2053V variant with an intermediate phenotype of congenital hypotonia, keloids, elevated creatinine kinase and contractures in the elbow, wrist, fingers, knee and ankle joints. The G2053V variant was not observed in approximately 6500 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 G2053V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, affecting the Glycine residue of the triple-helical region containing Gly-X-Y repeats. In silico analysis predicts this variant is probably damaging to the protein structure/function. A different missense variant at the same codon (G2053C), and another in a nearby residue (G2056R), have been reported in the Human Gene Mutation Database in association with COL6A3-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret G2053V as a pathogenic variant.
Invitae RCV001059032 SCV001223636 likely pathogenic Bethlem myopathy 1 2019-03-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 2053 of the COL6A3 protein (p.Gly2053Val). 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 in individuals affected with type VI collagenopathy (PMID: 24038877, 24907562). ClinVar contains an entry for this variant (Variation ID: 280028). 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 COL6A3, 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 (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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000334260 SCV001250157 pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing

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