NM_000377.3(WAS):c.134C>T (p.Thr45Met) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 18, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001037597.5

Allele description [Variation Report for NM_000377.3(WAS):c.134C>T (p.Thr45Met)]

NM_000377.3(WAS):c.134C>T (p.Thr45Met)

Gene:

WAS:WASP actin nucleation promoting factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.23

Genomic location:

Preferred name:

NM_000377.3(WAS):c.134C>T (p.Thr45Met)

HGVS:

NC_000023.11:g.48684284C>T
NG_007877.1:g.5488C>T
NM_000377.3:c.134C>TMANE SELECT
NP_000368.1:p.Thr45Met
NP_000368.1:p.Thr45Met
LRG_125t1:c.134C>T
LRG_125:g.5488C>T
LRG_125p1:p.Thr45Met
NC_000023.10:g.48542673C>T
NM_000377.2:c.134C>T
P42768:p.Thr45Met

Protein change:

T45M; THR45MET

Links:

UniProtKB: P42768#VAR_008106; OMIM: 300392.0010; dbSNP: rs132630273

NCBI 1000 Genomes Browser:

rs132630273

Molecular consequence:

NM_000377.3:c.134C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: X-linked severe congenital neutropenia (SCNX)
Identifiers:: MONDO: MONDO:0010294; MedGen: C1845987; Orphanet: 86788; OMIM: 300299

Name:: Thrombocytopenia 1
Synonyms:: THROMBOCYTOPENIA, X-LINKED, 1; Thrombocytopenia, X-linked; X-linked thrombocytopenia with normal platelets
Identifiers:: MONDO: MONDO:0010743; MedGen: C1839163; Orphanet: 268322; OMIM: 313900

Name:: Wiskott-Aldrich syndrome (WAS)
Synonyms:: Eczema thrombocytopenia immunodeficiency syndrome; Immunodeficiency 2; IMD 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010518; MedGen: C0043194; Orphanet: 906; OMIM: 301000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001201020	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 18, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 19817875, 23160469, 7753869, 8757563, 9326235, 11167787, 12969986, 15284122, 21185603, 28641574, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001201020

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 18, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterization of Wiskott-Aldrich syndrome (WAS) mutants using Saccharomyces cerevisiae.

Rajmohan R, Raodah A, Wong MH, Thanabalu T.

FEMS Yeast Res. 2009 Dec;9(8):1226-35. doi: 10.1111/j.1567-1364.2009.00581.x. Epub 2009 Sep 7.

PubMed [citation]

PMID:: 19817875

Disease-associated missense mutations in the EVH1 domain disrupt intrinsic WASp function causing dysregulated actin dynamics and impaired dendritic cell migration.

Worth AJ, Metelo J, Bouma G, Moulding D, Fritzsche M, Vernay B, Charras G, Cory GO, Thrasher AJ, Burns SO.

Blood. 2013 Jan 3;121(1):72-84. doi: 10.1182/blood-2012-01-403857. Epub 2012 Nov 15.

PubMed [citation]

PMID:: 23160469
PMCID:: PMC3779380

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001201020.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Experimental studies have shown that this missense change affects WAS function (PMID: 19817875, 23160469). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 11123). This variant is also known as 168C>T. This missense change has been observed in individual(s) with Wiskott-Aldrich syndrome (PMID: 7753869, 8757563, 9326235, 11167787, 12969986, 15284122, 21185603, 28641574). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 45 of the WAS protein (p.Thr45Met).

#	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: Nov 24, 2024

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