Submissions for variant NM_014795.4(ZEB2):c.1426dup (p.Met476fs)

dbSNP: rs587776604

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000005023	SCV000249483	pathogenic	Mowat-Wilson syndrome	2013-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000498048	SCV000589558	pathogenic	not provided	2018-07-10	criteria provided, single submitter	clinical testing	The c.1426dupA variant in the ZEB2 gene has been reported previously (as 1421 insA in the SIP1 gene due to alternate nomenclature) in an individual with Mowat-Wilson syndrome described as syndromic Hirschsprung disease with intellectual disability, microcephaly, facial dysmorphism and other anomalies (Cacheux et al., 2001; Dastot-Le Moal et al., 2007). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1426dupA variant causes a frameshift starting with codon Methionine 476, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Met476AsnfsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Eurofins Ntd Llc (ga)	RCV000498048	SCV000854809	pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005023	SCV002045648	pathogenic	Mowat-Wilson syndrome	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000005023	SCV002226970	pathogenic	Mowat-Wilson syndrome	2021-08-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 4757). This variant is also known as 1421insA . This premature translational stop signal has been observed in individual(s) with Mowat-Wilson syndrome (PMID: 11448942, 27831545). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met476Asnfs*6) 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).
Ambry Genetics	RCV002390091	SCV002698438	pathogenic	Inborn genetic diseases	2019-05-04	criteria provided, single submitter	clinical testing	The c.1426dupA pathogenic mutation (also referred to as 1421insA), located in coding exon 7 of the ZEB2 gene, results from a duplication of A at nucleotide position 1426, causing a translational frameshift with a predicted alternate stop codon (p.M476Nfs*6). This pathogenic mutation was identified in one patient from a cohort with Hirschsprung disease, intellectual disability, microcephaly, and distinctive facial phenotype (Cacheux V et al. Hum. Mol. Genet., 2001 Jul;10:1503-10). Additional features observed in this individual have been described in other publications, and include: heart defect (pulmonary atresia, ventricular septal defect, dysplastic mitral valve), failure-to-thrive, and seizures (Mowat DR et al. J. Med. Genet., 1998 Aug;35:617-23), broad halluces, submucous cleft, depigmentation, autonomic dysregulation (Dastot-Le Moal F et al. Hum. Mutat., 2007 Apr;28:313-21), and brain MRI findings of partial agenesis of the corpus callosum, ventricular temporal horn enlargement, and hippocampal abnormalities (Garavelli L et al. Genet. Med., 2017 06;19:691-700). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000005023	SCV003761407	pathogenic	Mowat-Wilson syndrome	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Met476AsnfsTer6 variant in ZEB2 was identified by our study in one individual with agenesis of the corpus callosum, seizures, and global developmental delay. Trio exome analysis showed this variant to be de novo. The p.Met476AsnfsTer6 variant in ZEB2 has been previously reported in one individual with Mowat Wilson syndrome (PMID: 11448942). 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: 4757) and has been interpreted as pathogenic by multiple submitters. 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 476 and leads to a premature termination codon 6 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).
OMIM	RCV000005023	SCV000025199	pathogenic	Mowat-Wilson syndrome	2001-07-01	no assertion criteria provided	literature only