Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000159481 | SCV000209433 | uncertain significance | not provided | 2013-05-16 | criteria provided, single submitter | clinical testing | This variant is denoted p.Leu875Arg at the protein level, c.2624 T>G at the cDNA level, and results in the change of a Leucine for an Arginine (CTG>CGG) in exon 8 of the ZEB2 gene (NM_014795.2). The Leu875Arg 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. The amino acid substitution is non-conservative, as an uncharged, non-polar Leucine residue is replaced by a positively charged Arginine residue. It alters a position that is conserved through mammals but is not conserved in more distant species through evolution. 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). One in silico algorithm predicts Leu875Arg may be benign, while other models suggest it may be damaging to protein structure/function. Therefore, based on the currently available information, it is unclear whether Leu875Arg is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). |
| Labcorp Genetics |
RCV003611501 | SCV004455746 | uncertain significance | Mowat-Wilson syndrome | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 875 of the ZEB2 protein (p.Leu875Arg). This variant is not present in population databases (gnomAD no frequency). 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: 181741). 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 not expected to disrupt ZEB2 protein function with a negative predictive value of 80%. 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. |