Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000378927 | SCV000330856 | pathogenic | not provided | 2016-10-04 | criteria provided, single submitter | clinical testing | The G291E variant in the EDA gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The G291E variant was not observed in approximately 6500 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 G291E 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. In addition, 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 the same residue (G291R and G291W) 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. We interpret G291E as a pathogenic variant. |
| Labcorp Genetics |
RCV001347864 | SCV001542145 | pathogenic | Hypohidrotic X-linked ectodermal dysplasia | 2022-02-08 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly291 amino acid residue in EDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9736768, 20979233, 21357618). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 280902). This missense change has been observed in individual(s) with clinical features of ectodermal dysplasia (Invitae; external communication). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 291 of the EDA protein (p.Gly291Glu). |