ClinVar

Description

The heterozygous p.Phe628LeufsTer18 variant in ZEB2 was identified by our study in one individual with agenesis of the corpus callosum and seizure. Trio exome analysis showed this variant to be de novo. The p.Phe628LeufsTer18 variant in ZEB2 has been previously reported in 2 unrelated individuals with Mowat Wilson syndrome (PMID: 19842203, PMID: 17203459). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant has also been reported in ClinVar (Variation ID: 189277) and has been interpreted as pathogenic by Children’s Mercy Hospital and Clinics Molecular Genetics Laboratory and as likely pathogenic by Genomics England. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 628 and leads to a premature termination codon 18 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the ZEB2 gene is an established disease mechanism in autosomal dominant Mowat Wilson syndrome. In summary, this variant meets criteria to be classified as pathogenic for Mowat Wilson syndrome. ACMG/AMP Criteria applied: PVS1, PS2_Supporting, PS4_Supporting, PM2_Supporting (Richards 2015).