Submissions for variant NM_014795.4(ZEB2):c.904C>T (p.Arg302Ter)

dbSNP: rs587784571

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000148007	SCV000195505	pathogenic	Mowat-Wilson syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000167554	SCV000209418	pathogenic	not provided	2017-06-15	criteria provided, single submitter	clinical testing	The R302X variant in the ZEB2 gene has been reported previously in a few unrelated individuals with clinical features of Mowat-Wilson syndrome (Ishihara et al., 2004; Saunders et al., 2009; Jiang et al., 2017). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R302X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R302X as a pathogenic variant.
Invitae	RCV000148007	SCV001414045	pathogenic	Mowat-Wilson syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg302*) in the ZEB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ZEB2 are known to be pathogenic (PMID: 16053902). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Mowat-Wilson syndrome (PMID: 15121779, 19842203). ClinVar contains an entry for this variant (Variation ID: 160329). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000148007	SCV002020931	pathogenic	Mowat-Wilson syndrome	2021-04-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000148007	SCV002045652	pathogenic	Mowat-Wilson syndrome	2021-11-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000148007	SCV003761408	pathogenic	Mowat-Wilson syndrome	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Arg302Ter variant in ZEB2 was identified by our study in one individual with periventricular heterotopia, agenesis of the corpus callosum, and seizures. Trio exome analysis showed this variant to be de novo. The p.Arg302Ter variant in ZEB2 has been previously reported in at least 4 unrelated individuals with Mowat Wilson syndrome (PMID: 28096981, PMID: 29093530, PMID: 15121779, PMID: 19842203). The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 2 individuals with confirmed paternity and maternity (PMID: 28096981, PMID: 29093530). This variant has also been reported in ClinVar (Variation ID: 160329) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 302, which is 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, PS4_Moderate, PM2_Supporting (Richards 2015).
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000167554	SCV000218433	pathogenic	not provided	2015-01-30	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000148007	SCV000221244	pathogenic	Mowat-Wilson syndrome	2015-03-02	no assertion criteria provided	clinical testing