ClinVar Miner

Submissions for variant NM_006397.2(RNASEH2A):c.760T>C (p.Trp254Arg) (rs757666508)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519024 SCV000620275 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing The W254R variant in the RNASEH2A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The W254R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The W254R 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret W254R as a variant of uncertain significance.
Invitae RCV001208798 SCV001380205 uncertain significance Aicardi Goutieres syndrome 4 2019-09-05 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 254 of the RNASEH2A protein (p.Trp254Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs757666508, ExAC 0.002%). This variant has not been reported in the literature in individuals with RNASEH2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 451556). 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: "Tolerated"; 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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