ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.646C>T (p.Pro216Ser) (rs1556098806)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521166 SCV000620024 likely pathogenic not provided 2017-08-15 criteria provided, single submitter clinical testing The P216S variant in the EDA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P216S 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. Missense variants in nearby residues (T211R, G215R, G218D, P220L, G221D) have been reported in the Human Gene Mutation Database in association with hypohidrotic ectodermal dysplasia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret P216S as a likely pathogenic variant.
Invitae RCV001212052 SCV001383625 uncertain significance Hypohidrotic X-linked ectodermal dysplasia 2019-07-30 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 216 of the EDA protein (p.Pro216Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with EDA-related conditions. ClinVar contains an entry for this variant (Variation ID: 451339). 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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