ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.617C>T (p.Pro206Leu) (rs1057520742)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000439320 SCV000517258 pathogenic not provided 2015-05-15 criteria provided, single submitter clinical testing The P206L variant has not been published as pathogenic, nor has it been reported as a benign polymorphismto our knowledge. It was not observed in approximately 6,500 individuals of European and African Americanancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in thesepopulation. P206L is a semi-conservative amino acid substitution, which may impact secondary proteinstructure as these residues differ in some properties. This substitution occurs at a position that is conservedacross species and in-silico analysis predicts this variant is probably damaging to the proteinstructure/function. In addition, missense variants in nearby residues (G198R/A, G207R/V, P209L, T211R)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. Therefore, we interpret this variant as pathogenic.
Invitae RCV000526582 SCV000630032 likely pathogenic Hypohidrotic X-linked ectodermal dysplasia 2016-08-12 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 206 of the EDA protein (p.Pro206Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a EDA-related disease. Family studies indicate this missense variant likely was not inherited from either parent (i.e. occurred de novo) in an affected individual. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. For these reasons, this variant has been classified as Likely Pathogenic.

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