Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000439291 | SCV000524543 | likely pathogenic | not provided | 2016-02-11 | criteria provided, single submitter | clinical testing | The Y144C variant in the FOXE3 gene, located in the forkhead protein domain, has not been reported previously as apathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. The Y144C 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 otherproperties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts thisvariant is probably damaging to the protein structure/function. The Y144C variant is a strong candidate for apathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Labcorp Genetics |
RCV001861538 | SCV002273596 | uncertain significance | Congenital primary aphakia; Anterior segment dysgenesis | 2022-08-15 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 144 of the FOXE3 protein (p.Tyr144Cys). This variant is present in population databases (rs747148416, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FOXE3-related conditions. ClinVar contains an entry for this variant (Variation ID: 383926). 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 FOXE3 protein function. 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. |