ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.2968G>A (p.Gly990Arg) (rs1040238147)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483758 SCV000573632 likely pathogenic not provided 2018-01-18 criteria provided, single submitter clinical testing The G990R variant in the COL5A2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G990R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G990R 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 Glycine residue of a Gly-X-Y repeat within the triple-helical region, at position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G990R as a strong candidate for a pathogenic variant; however, the possibility that it may be a rare benign variant cannot be completely excluded.
Invitae RCV000816976 SCV000957508 uncertain significance Ehlers-Danlos syndrome, classic type 2019-01-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 990 of the COL5A2 protein (p.Gly990Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 423881). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C65"). 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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