ClinVar Miner

Submissions for variant NM_001844.5(COL2A1):c.1546G>A (p.Gly516Ser) (rs886041895)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000274274 SCV000330688 pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing A novel G516S pathogenic variant was identified in the COL2A1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. G516S occurs in the triple helical domain and replaces the Glycine in the canonical Gly-X-Y repeat. Mutations in these Glycines result in poor winding of the collagen triple helix and a less functional protein. The G516S variant is not observed in large population cohorts. The G516S 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 damaging to the protein structure/function. Another missense variant affecting the same residue (G516D) and missense variants in nearby Glycine residues (G510D, G513S, G519S, G522V) have been reported in the Human Gene Mutation Database in association with COL2A1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, the presence of this pathogenic variant is consistent with the diagnosis of a COL2A1-related skeletal dysplasia.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000274274 SCV001447012 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing

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