NM_014795.4(ZEB2):c.2761C>T (p.Arg921Ter) AND Mowat-Wilson syndrome

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Jan 25, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000147998.30

Allele description [Variation Report for NM_014795.4(ZEB2):c.2761C>T (p.Arg921Ter)]

NM_014795.4(ZEB2):c.2761C>T (p.Arg921Ter)

Gene:

ZEB2:zinc finger E-box binding homeobox 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q22.3

Genomic location:

Preferred name:

NM_014795.4(ZEB2):c.2761C>T (p.Arg921Ter)

Other names:

p.R921*:CGA>TGA; NM_014795.4(ZEB2):c.2761C>T; p.Arg921Ter

HGVS:

NC_000002.12:g.144398426G>A
NG_016431.1:g.126966C>T
NM_001171653.2:c.2689C>T
NM_014795.4:c.2761C>TMANE SELECT
NP_001165124.1:p.Arg897Ter
NP_055610.1:p.Arg921Ter
NC_000002.11:g.145155993G>A
NM_014795.3:c.2761C>T

Protein change:

R897*

Links:

dbSNP: rs587784566

NCBI 1000 Genomes Browser:

rs587784566

Molecular consequence:

NM_001171653.2:c.2689C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_014795.4:c.2761C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Mowat-Wilson syndrome (MOWS)
Synonyms:: Mental retardation, microcephaly, and distinct facial features with or without Hirschsprung disease; Hirschsprung disease mental retardation syndrome
Identifiers:: MONDO: MONDO:0009341; MedGen: C1856113; Orphanet: 2152; OMIM: 235730

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195495	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000680438	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Oct 24, 2017)	de novo	clinical testing	Citation Link,
SCV001218240	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 25, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19215041, 24401652, 24715670, 26809768, 16053902, 28492532
SCV002020933	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 13, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002045643	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003761404	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 25, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	de novo	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature.

Garavelli L, Zollino M, Mainardi PC, Gurrieri F, Rivieri F, Soli F, Verri R, Albertini E, Favaron E, Zignani M, Orteschi D, Bianchi P, Faravelli F, Forzano F, Seri M, Wischmeijer A, Turchetti D, Pompilii E, Gnoli M, Cocchi G, Mazzanti L, Bergamaschi R, et al.

Am J Med Genet A. 2009 Mar;149A(3):417-26. doi: 10.1002/ajmg.a.32693. Review.

PubMed [citation]

PMID:: 19215041

See all PubMed Citations (8)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000195495.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000680438.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	1	blood	not provided		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001218240.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 160323). This premature translational stop signal has been observed in individual(s) with Mowat-Wilson syndrome (PMID: 16053902, 19215041, 24401652, 24715670, 26809768). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg921*) 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020933.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002045643.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761404.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The heterozygous p.Arg921Ter variant in ZEB2 was identified by our study in one individual with abnormalities of the corpus callosum. Trio exome analysis showed this variant to be de novo. The p.Arg921Ter variant in ZEB2 has been previously reported in 16 unrelated individuals with Mowat Wilson syndrome (PMID: 17203459, PMID: 33619735, PMID: 33199988, PMID: 32593896, PMID: 24401652, PMID: 26809768, PMID: 24715670, PMID: 19215041, PMID: 16053902, SCV001437886.1, SCV000680438.1). 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 6 individuals with confirmed paternity and maternity (PMID: 33619735, PMID: 33199988, PMID: 24401652, PMID: 16053902, SCV001437886.1, SCV000680438.1). This variant has also been reported in ClinVar (Variation ID: 160323) 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 921, 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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