Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000255050 | SCV000321585 | pathogenic | not provided | 2015-12-23 | criteria provided, single submitter | clinical testing | The A349T variant has been previously published in association with X-linked HED (Monreal et al., 1998; Na et al., 2004; He et al., 2013). 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. A349T 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 (C346Y, G350D, L354P) have been reported in the Human Gene Mutation Database in association with HED (Stenson et al., 2014), supporting the functional importance of this region of the protein. Additionally, EDA1 has a low rate of benign missense variation and missense variants are a common mechanism of disease in this gene. Females who are heterozygous for EDA1 pathogenic variants can show variable phenotypic expression of the disorder, ranging from being virtually asymptomatic to having full expression of the disease. |
| Invitae | RCV000011787 | SCV001235748 | pathogenic | Hypohidrotic X-linked ectodermal dysplasia | 2019-02-23 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with threonine at codon 349 of the EDA protein (p.Ala349Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with ectodermal dysplasia (PMID: 9683615, 15461765). ClinVar contains an entry for this variant (Variation ID: 11040). 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 and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. |
| OMIM | RCV000011787 | SCV000032019 | pathogenic | Hypohidrotic X-linked ectodermal dysplasia | 1998-08-01 | no assertion criteria provided | literature only |