Submissions for variant NM_014795.4(ZEB2):c.2083C>T (p.Arg695Ter)

dbSNP: rs137852981

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000213082	SCV000113591	pathogenic	not provided	2014-04-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000005021	SCV000195489	pathogenic	Mowat-Wilson syndrome	2013-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000213082	SCV000209428	pathogenic	not provided	2020-04-30	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24401652, 17932455, 11279515, 26809768, 23891399, 31285160, 25525159, 11592033, 15908750, 27831545, 32196960, 33510600)
Fulgent Genetics, Fulgent Genetics	RCV000005021	SCV000611336	pathogenic	Mowat-Wilson syndrome	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000005021	SCV000641870	pathogenic	Mowat-Wilson syndrome	2020-01-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ZEB2 are known to be pathogenic (PMID: 16053902). This variant has been observed in several individuals affected with Mowat-Wilson syndrome (PMID: 27831545, 17932455, 26809768, 19842203, 17958891) including many de novo observations (PMID: 11592033, 15908750, 24401652, 26993267). This variant is also known as c.2083C>T (p.R925X), and this gene is also known as the SIP1 and ZFHX1B in the literature. ClinVar contains an entry for this variant (Variation ID: 4755). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg695*) in the ZEB2 gene. It is expected to result in an absent or disrupted protein product.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000005021	SCV000778534	pathogenic	Mowat-Wilson syndrome	2018-03-27	criteria provided, single submitter	research
Baylor Genetics	RCV000005021	SCV000807292	pathogenic	Mowat-Wilson syndrome	2017-09-01	criteria provided, single submitter	clinical testing	This variant was previously reported as pathogenic and was found once in our laboratory in a 17-year-old male with intellectual disability, absent speech, epilepsy, self-injury, aortic stenosis, hypospadias, Hirschsprung disease, quadriplegic cerebral palsy.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000005021	SCV000999310	pathogenic	Mowat-Wilson syndrome		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005021	SCV002045645	pathogenic	Mowat-Wilson syndrome	2021-11-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000005021	SCV003761405	pathogenic	Mowat-Wilson syndrome	2023-01-25	criteria provided, single submitter	curation	The p.Arg695Ter variant in ZEB2 was identified by our study in one individual with global developmental delay and agenesis of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Arg695Ter variant in ZEB2 has been previously reported in 16 unrelated individuals with Mowat Wilson syndrome (PMID: 33510600, PMID: 32196960, PMID: 27831545, PMID: 15908750, PMID: 11592033, PMID: 31285160, PMID: 26809768, PMID: 11279515, PMID: 17932455, PMID: 24401652). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 7 individuals with confirmed paternity and maternity (PMID: 33510600, PMID: 15908750, PMID: 11592033, PMID: 11279515, PMID: 24401652). This variant has also been reported in ClinVar (Variation ID: 4755) 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 695, 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_VeryStrong, PS4, PM2_Supporting (Richards 2015).
3billion	RCV000005021	SCV003841966	pathogenic	Mowat-Wilson syndrome	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004755 / PMID: 11592033). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Medical Genetics Unit, Azienda USL-IRCCS di Reggio Emilia	RCV000005021	SCV004231868	pathogenic	Mowat-Wilson syndrome	2023-10-20	criteria provided, single submitter	clinical testing	Heterozygous variant associated with Mowat-Wilson syndrome in various individuals (de novo / germline mosaicism). ACMG/AMP criteria PVS1, PS2, PM2, PP4
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000005021	SCV005087228	pathogenic	Mowat-Wilson syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Mowat-Wilson syndrome (MIM#235730). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID:29300384). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000005021	SCV000025197	pathogenic	Mowat-Wilson syndrome	2001-12-01	no assertion criteria provided	literature only
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000005021	SCV000221248	pathogenic	Mowat-Wilson syndrome	2015-03-02	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000213082	SCV001797690	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000213082	SCV001957408	pathogenic	not provided		no assertion criteria provided	clinical testing