Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000809933 | SCV000271217 | likely pathogenic | Hypohidrotic X-linked ectodermal dysplasia | 2015-01-26 | criteria provided, single submitter | clinical testing | The p.Ala356Val variant in EDA has been reported in 2 individuals with clinical features of X-linked hypohidrotic ectodermaldysplasia (XLHED)(Clauss 2010, Cluze au 2011) and was absent from large population studies. In addition, a different amino acid change at the same position (p.Ala356Asn) has been identified in 1 ma le with XLHED suggesting that a change at this position may not be tolerated (Mo nreal 2008). Computational prediction tools and conservation analysis suggest th at the p.Ala356Val variant may impact the protein, though this information is no t predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Ala356V al variant is likely pathogenic. |
| Invitae | RCV000809933 | SCV000950116 | pathogenic | Hypohidrotic X-linked ectodermal dysplasia | 2018-11-19 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala356 amino acid residue in EDA. Other variant(s) that disrupt this residue have been observed in individuals with EDA-related conditions (PMID: 9683615, 11279189), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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. This variant has been observed in an individual affected with hypohidrotic ectodermal dysplasia (PMID: 20979233). ClinVar contains an entry for this variant (Variation ID: 228255). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 356 of the EDA protein (p.Ala356Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. |