Submissions for variant NM_014795.4(ZEB2):c.3095del (p.Cys1032fs)

dbSNP: rs1060500653

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477195	SCV000543401	pathogenic	Mowat-Wilson syndrome	2020-10-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the ZEB2 protein. Other variant(s) that disrupt this region (p.Arg1047Serfs*32, also known as H1049fsX1080) have been determined to be pathogenic (PMID: 16053902, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has not been reported in the literature in individuals with ZEB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 405331). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys1032Leufs*43) in the ZEB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 183 amino acid(s) of the ZEB2 protein.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000477195	SCV003761401	likely pathogenic	Mowat-Wilson syndrome	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Cys1032LeufsTer43 variant in ZEB2 was identified by our study in one individual with partial agenesis of the corpus callosum, polymicrogyria, and seizure. Trio exome analysis showed this variant to be de novo. The p.Cys1032LeufsTer43 variant in ZEB2 has not been previously reported in the literature in individuals with Mowat Wilson syndrome. This variant has also been reported in ClinVar (Variation ID: 405331) and has been interpreted as pathogenic by Invitae. 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 1032 and leads to a premature termination codon 43 amino acids downstream. This termination codon occurs within the terminal 50 bases of the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Heterozygous loss of function of the ZEB2 gene is an established disease mechanism in autosomal dominant Mowat Wilson syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for Mowat Wilson syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PS2_Supporting, PM2_Supporting (Richards 2015).