Submissions for variant NM_001399.5(EDA):c.466C>T (p.Arg156Cys)

dbSNP: rs132630313

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414306	SCV000490519	pathogenic	not provided	2018-08-30	criteria provided, single submitter	clinical testing	The R156C missense change in the EDA1 gene has been published previously and seen many times at GeneDx in association with X-linked hypohidrotic ectodermal dysplasia (HED) (Monreal et al., 1998; Cluzeau et al., 2011; Burger et al., 2014). It 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. The R156C 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 in mammals and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same (R156S/L/H) and in nearby residues (R153C/H, R155C, K158N) have been reported in the Human Gene Mutation Database in association with ectodermal dysplasia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, functional studies of the R156C variant have shown that it prevents degradation of EDA (Schneider et al., 2001).
Invitae	RCV000011783	SCV000630026	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2023-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the EDA protein (p.Arg156Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypohidrotic or anhidrotic ectodermal dysplasia (PMID: 9683615, 9736768, 11378824, 18231121, 20979233). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11036). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EDA protein function. Experimental studies have shown that this missense change affects EDA function (PMID: 11279189, 11416205). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000011783	SCV002572725	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.55; 3Cnet: 0.90). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011036). Different missense changes at the same codon (p.Arg156His, p.Arg156Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011037 , VCV000044194). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
PreventionGenetics, part of Exact Sciences	RCV003390668	SCV004119031	likely pathogenic	EDA-related condition	2022-09-09	criteria provided, single submitter	clinical testing	The EDA c.466C>T variant is predicted to result in the amino acid substitution p.Arg156Cys. This variant has been reported to be causative for X-linked hypohidrotic ectodermal dysplasia (Bayés et al. 1998. PubMed ID: 9736768; Monreal et al. 1998. PubMed ID: 9683615). In addition, other missense variants affecting the same amino acid have been reported in individuals with ectodermal dysplasia (Clauss et al. 2010. PubMed ID: 20236127; Aoki et al. 2000. PubMed ID: 10951256). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
OMIM	RCV000011783	SCV000032015	pathogenic	Hypohidrotic X-linked ectodermal dysplasia	1998-08-01	no assertion criteria provided	literature only