ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.1069C>T (p.Arg357Trp) (rs886039347)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255432 SCV000321586 pathogenic not provided 2016-03-30 criteria provided, single submitter clinical testing The R357W pathogenic variant in the EDA1 gene has been reported previously in association with ectodermal dysplasia (Arte et al., 2013) and has been observed in multiple affected individuals at GeneDx. The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. R357W 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 within the TNF homology domain that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same codon (R357P) and in nearby residues (L354P, A356D, Q358E/H, I360N) have been reported in the Human Gene Mutation Database in association with EDA1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of nearby variants in the TNF homology domain have shown them to have adverse effects on protein function (Mues et al., 2010).
Invitae RCV000532383 SCV000630018 uncertain significance Hypohidrotic X-linked ectodermal dysplasia 2019-10-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 357 of the EDA protein (p.Arg357Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of X-linked hypohidrotic ectodermal dysplasia (PMID: 23991204, 28045201, Invitae). ClinVar contains an entry for this variant (Variation ID: 265112). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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