NM_014795.4(ZEB2):c.2707G>A (p.Ala903Thr) AND Mowat-Wilson syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 23, 2022
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:: RCV001043762.10

Allele description [Variation Report for NM_014795.4(ZEB2):c.2707G>A (p.Ala903Thr)]

NM_014795.4(ZEB2):c.2707G>A (p.Ala903Thr)

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.2707G>A (p.Ala903Thr)

HGVS:

NC_000002.12:g.144398480C>T
NG_016431.1:g.126912G>A
NM_001171653.2:c.2635G>A
NM_014795.4:c.2707G>AMANE SELECT
NP_001165124.1:p.Ala879Thr
NP_055610.1:p.Ala903Thr
NC_000002.11:g.145156047C>T
NM_014795.3:c.2707G>A

Protein change:

A879T

Links:

dbSNP: rs730881200

NCBI 1000 Genomes Browser:

rs730881200

Molecular consequence:

NM_001171653.2:c.2635G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014795.4:c.2707G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001207523	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004047999	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001207523

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 23, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004047999

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

clinical testing

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	germline	yes	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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001207523.5

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

Description

This variant has not been reported in the literature in individuals affected with ZEB2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 841521). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 903 of the ZEB2 protein (p.Ala903Thr).

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047999.1

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

Description

The missense c.2707G>A (p.Ala903Thr) variant in ZEB2 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The variant is observed in 0.0003% alleles in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Ala at position 903 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala903Thr in ZEB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance

#	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

Last Updated: Sep 29, 2024

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