Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000159467 | SCV000209416 | uncertain significance | not provided | 2013-10-02 | criteria provided, single submitter | clinical testing | This variant is denoted as p.Arg222Cys at the protein level, c.664 C>T at the cDNA level and results in the change of an Arginine to a Cysteine (CGC>TGC) in exon 6 of the ZEB2 gene (NM_014795.2). The Arg222Cys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. 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. This variant is a non-conservative amino acid substitution of a positively charged Arginine residue with an uncharged Cysteine residue, and the addition of a Cysteine residue, which affects disulfide bonds, may alter the secondary structure of the protein. The variant alters a position in the protein that is conserved across species, and in silico analysis predicts this variant is possibly damaging to the protein structure/function. However, missense mutations in the ZEB2 gene are rare and have been identified in less than 2% of patients with Mowat-Wilson syndrome (Garavelli et al., 2009). Therefore, based on the currently available information, it is unclear whether Arg222Cys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Invitae | RCV003502518 | SCV004330890 | uncertain significance | Mowat-Wilson syndrome | 2023-10-08 | 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 222 of the ZEB2 protein (p.Arg222Cys). This variant is present in population databases (rs730881189, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ZEB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 181728). 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 ZEB2 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. |