ClinVar Miner

Submissions for variant NM_001399.5(EDA):c.476G>C (p.Arg159Thr) (rs1556039084)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544580 SCV000630028 uncertain significance Hypohidrotic X-linked ectodermal dysplasia 2017-08-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 159 of the EDA protein (p.Arg159Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. 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 disease. 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: "Benign"; Align-GVGD: "Class C0"). While functional evidence is not available for this particular missense change, experimental studies on a different amino acid change at the same codon (p.Arg159Ala) have shown that this particular change inhibits processing of the EDA protein by furin. This suggests that this codon Arg159 is critical for proper cleavage of the EDA protein, which is necessary for its function in mediating downstream signaling pathways (PMID: 11416205). 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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