Submissions for variant NM_014795.4(ZEB2):c.1027C>T (p.Arg343Ter)

dbSNP: rs786204815

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723419	SCV000232736	pathogenic	not provided	2014-05-18	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000169715	SCV000249481	pathogenic	Mowat-Wilson syndrome	2015-02-23	criteria provided, single submitter	clinical testing
Invitae	RCV000169715	SCV001221054	pathogenic	Mowat-Wilson syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg343*) 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: 12784289, 15121779, 19842203, 24715670). ClinVar contains an entry for this variant (Variation ID: 189281). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266280	SCV001444453	pathogenic	Inborn genetic diseases	2021-06-17	criteria provided, single submitter	clinical testing	The c.1027C>T (p.R343*) alteration, located in exon 8 (coding exon 7) of the ZEB2 gene, consists of a C to T substitution at nucleotide position 1027. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 343. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD), the ZEB2 c.1027C>T alteration was not observed, with coverage at this position. This alteration has been detected in several individuals with symptoms consistent with Mowat Wilson syndrome (Wilson, 2003; Zweier, 2005; Yamada, 2014; Paz, 2015). An 18 year old male reported by Wilson et al. (2003) had intellectual disability, epilepsy, microcephaly, tetralogy of Fallot, hypospadias, and pelvi-ureteric junction obstruction._x000D_ _x000D_ reminder to manually add internal co-seg data to report Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV000723419	SCV002031008	pathogenic	not provided	2021-11-30	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: 25525159, 12784289, 31376723, 15384097, 19842203, 24715670, 25608121, 25899569, 16053902)
Genome-Nilou Lab	RCV000169715	SCV002045651	pathogenic	Mowat-Wilson syndrome	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169715	SCV002050742	pathogenic	Mowat-Wilson syndrome	2021-12-01	criteria provided, single submitter	clinical testing	Variant summary: ZEB2 c.1027C>T (p.Arg343X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 251184 control chromosomes (gnomAD). c.1027C>T has been reported in the literature in multiple individuals affected with Mowat-Wilson Syndrome (examples: Wilson_2003, Ishihara_2004, Yamada_2014, Schuster_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed this variant after 2014, and all submissions have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000169715	SCV002051772	pathogenic	Mowat-Wilson syndrome	2021-12-02	criteria provided, single submitter	clinical testing
Molecular Genetics Laboratory, Children's Mercy Hospital and Clinics	RCV000169715	SCV000221254	pathogenic	Mowat-Wilson syndrome	2015-03-02	no assertion criteria provided	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV000169715	SCV001428403	pathogenic	Mowat-Wilson syndrome	2019-01-01	no assertion criteria provided	clinical testing