VCV000011123.40 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(6); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 11123 Accession: VCV000011123.40

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xp11.23 X: 48684284 (GRCh38) [ NCBI UCSC ] X: 48542673 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 15, 2018	Nov 24, 2024	Sep 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000377.3:c.134C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000368.1:p.Thr45Met	missense
NC_000023.11:g.48684284C>T
NC_000023.10:g.48542673C>T
NG_007877.1:g.5488C>T
LRG_125:g.5488C>T
LRG_125t1:c.134C>T	LRG_125p1:p.Thr45Met
	P42768:p.Thr45Met

... more HGVS ... less HGVS

Protein change

T45M

Other names

Canonical SPDI

NC_000023.11:48684283:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs132630273 ClinGen: CA255728 UniProtKB: P42768#VAR_008106 OMIM: 300392.0010 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
WAS		-	-	GRCh38 GRCh37	625	799

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Thrombocytopenia 1	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 8, 2023	RCV000011872.6
Thrombocytopenia	Pathogenic (1)	criteria provided, single submitter	Feb 1, 2019	RCV000851684.2
Thrombocytopenia 1 Wiskott-Aldrich syndrome X-linked severe congenital neutropenia	Pathogenic (1)	criteria provided, single submitter	Jul 18, 2023	RCV001037597.5
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 1, 2023	RCV001172206.25
WAS-related disorder	Pathogenic (1)	no assertion criteria provided	Apr 25, 2024	RCV004748516.1
Wiskott-Aldrich syndrome	Uncertain significance (1)	criteria provided, single submitter	May 20, 2023	RCV004760326.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Thrombocytopenia Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Study: ThromboGenomics Accession: SCV000899484.1 First in ClinVar: Sep 29, 2019 Last updated: Sep 29, 2019	Publications: PubMed (1) PubMed: 31064749 Sex: male Ethnicity/Population group: European
Pathogenic (Aug 29, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001778650.2 First in ClinVar: Aug 12, 2021 Last updated: Sep 07, 2023	Comment: Published functional studies demonstrate a damaging effect; reduces protein stability and ability to bind WIP (Worth et al., 2013); Not observed in large population cohorts … (more) Published functional studies demonstrate a damaging effect; reduces protein stability and ability to bind WIP (Worth et al., 2013); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8757563, 34705590, 31064749, 23160469, 11167787, 7753869, 28641574, 19817875, 31677488, 32814211, 35874699) (less)
Pathogenic (Jul 18, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Wiskott-Aldrich syndrome X-linked severe congenital neutropenia Thrombocytopenia 1 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001201020.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024	Publications: PubMed (10) PubMed: 19817875‚ 23160469‚ 7753869‚ 8757563‚ 9326235‚ 11167787‚ 12969986‚ 15284122‚ 21185603‚ 28641574 Comment: 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 … (more) 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). (less)
Uncertain significance (May 20, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Wiskott-Aldrich syndrome (X-linked recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005373655.2 First in ClinVar: Oct 13, 2024 Last updated: Nov 24, 2024	Comment: The observed missense c.134C>T(p.Thr45Met) variant in WAS gene has been reported previously in X-linked state in individual(s) affected with Wiskott-Aldrich syndrome (Yue et al., 2022). … (more) The observed missense c.134C>T(p.Thr45Met) variant in WAS gene has been reported previously in X-linked state in individual(s) affected with Wiskott-Aldrich syndrome (Yue et al., 2022). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The amino acid Thr at position 45 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr45Met in WAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing automatic) predict a damaging effect on protein structure and function for this variant. Experimental evidence indicated an impact on protein function and found that the variant partially impairs binding with WIP, an interaction proposed as causal to the disease (Rajmohan et al., 2009). For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of blood and blood-forming tissues (present)
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Thrombocytopenia 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002521743.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Publications: PubMed (11) PubMed: 19817875‚ 11167787‚ 21185603‚ 8757563‚ 28641574‚ 15284122‚ 7753869‚ 20546529‚ 12969986‚ 23160469‚ 9326235 Comment: The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene … (more) The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19817875, 23160469). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011123). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11167787, 12969986, 15284122, 21185603, 28641574, 7753869, 8757563, 9326235). A different missense change at the same codon (p.Thr45Lys) has been reported to be associated with WAS related disorder (PMID: 20546529). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Thrombocytopenia (present) , Purpura (present) , Ecchymosis (present) , Prolonged bleeding following circumcision (present)
Pathogenic (Mar 08, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Thrombocytopenia 1 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003922641.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Publications: PubMed (4) PubMed: 8757563‚ 11167787‚ 7753869‚ 19817875 Comment: Variant summary: WAS c.134C>T (p.Thr45Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: WAS c.134C>T (p.Thr45Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182571 control chromosomes (gnomAD). c.134C>T has been reported in the literature in the hemizygous state in multiple male individuals affected with X-Linked Thrombocytopenia, including at least one family in which the variant segregated with the disease phenotype (e.g. Kwan_1995, de Saint Basile_1996, Ho_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant partially impairs binding with WIP, an interaction proposed as causal to the disease (e.g. Rajmohan_2009). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Sep 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001335191.25 First in ClinVar: Jun 08, 2020 Last updated: Oct 20, 2024	Comment: WAS: PP1:Strong, PM2, PM5, PS4:Moderate, PS3:Supporting Number of individuals with the variant: 7
Pathogenic (Jan 01, 2001)	no assertion criteria provided Method: literature only	THROMBOCYTOPENIA, X-LINKED, 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000032105.3 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 8666397‚ 11167787 Comment on evidence: De Saint Basile et al. (1996) described a new mutation in a patient from a family with X-linked thrombocytopenia (THC1; 313900). Exon 2 products showed … (more) De Saint Basile et al. (1996) described a new mutation in a patient from a family with X-linked thrombocytopenia (THC1; 313900). Exon 2 products showed abnormal migration by single-strand conformational polymorphism analysis. A 168C-T transition produced a thr45-to-met missense mutation with no change in charge. Ho et al. (2001) found the thr45-to-met mutation in affected members of a large Syrian-Lebanese family with X-linked thrombocytopenia. Five family members had undergone splenectomy with rapid and sustained normalization of their platelet numbers. Ho et al. (2001) pointed out that exon 2 is the most common site for mutations associated with XLT and mild forms of WAS, and the 168C-T transition is the most frequent. (less)
Pathogenic (Apr 25, 2024)	no assertion criteria provided Method: clinical testing	WAS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361119.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The WAS c.134C>T variant is predicted to result in the amino acid substitution p.Thr45Met. This variant has been reported as causative for Wiskott-Aldrich syndrome (see … (more) The WAS c.134C>T variant is predicted to result in the amino acid substitution p.Thr45Met. This variant has been reported as causative for Wiskott-Aldrich syndrome (see for examples Kwan et al. 1995. PubMed ID: 7753869; Jin et al. 2004. PubMed ID: 15284122; Gulácsy et al. 2011. PubMed ID: 21185603). Functional studies indicate this variant decreases protein function (Worth et al. 2013. PubMed ID: 23160469). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11123). Given the evidence, we interpret c.134C>T (p.Thr45Met) as pathogenic. (less)

Comment:

Published functional studies demonstrate a damaging effect; reduces protein stability and ability to bind WIP (Worth et al., 2013); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8757563, 34705590, 31064749, 23160469, 11167787, 7753869, 28641574, 19817875, 31677488, 32814211, 35874699)

Comment:

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).

Comment:

The observed missense c.134C>T(p.Thr45Met) variant in WAS gene has been reported previously in X-linked state in individual(s) affected with Wiskott-Aldrich syndrome (Yue et al., 2022). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submitters). The amino acid Thr at position 45 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Thr45Met in WAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging, and MutationTaster - Disease causing automatic) predict a damaging effect on protein structure and function for this variant. Experimental evidence indicated an impact on protein function and found that the variant partially impairs binding with WIP, an interaction proposed as causal to the disease (Rajmohan et al., 2009). For these reasons, this variant has been classified as Pathogenic.

Comment:

The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19817875, 23160469). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.83; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000011123). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11167787, 12969986, 15284122, 21185603, 28641574, 7753869, 8757563, 9326235). A different missense change at the same codon (p.Thr45Lys) has been reported to be associated with WAS related disorder (PMID: 20546529). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Variant summary: WAS c.134C>T (p.Thr45Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182571 control chromosomes (gnomAD). c.134C>T has been reported in the literature in the hemizygous state in multiple male individuals affected with X-Linked Thrombocytopenia, including at least one family in which the variant segregated with the disease phenotype (e.g. Kwan_1995, de Saint Basile_1996, Ho_2001). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant partially impairs binding with WIP, an interaction proposed as causal to the disease (e.g. Rajmohan_2009). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The WAS c.134C>T variant is predicted to result in the amino acid substitution p.Thr45Met. This variant has been reported as causative for Wiskott-Aldrich syndrome (see for examples Kwan et al. 1995. PubMed ID: 7753869; Jin et al. 2004. PubMed ID: 15284122; Gulácsy et al. 2011. PubMed ID: 21185603). Functional studies indicate this variant decreases protein function (Worth et al. 2013. PubMed ID: 23160469). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/11123). Given the evidence, we interpret c.134C>T (p.Thr45Met) as pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic high-throughput sequencing of 2396 patients with bleeding, thrombotic, and platelet disorders.	Downes K	Blood	2019	PMID: 31064749
Intermittent low platelet counts hampering diagnosis of X-linked thrombocytopenia in children: report of two unrelated cases and a novel mutation in the gene coding for the Wiskott-Aldrich syndrome protein.	Medina SS	BMC pediatrics	2017	PMID: 28641574
Disease-associated missense mutations in the EVH1 domain disrupt intrinsic WASp function causing dysregulated actin dynamics and impaired dendritic cell migration.	Worth AJ	Blood	2013	PMID: 23160469
Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome.	Gulácsy V	Molecular immunology	2011	PMID: 21185603
Analysis of clinical and molecular characteristics of Wiskott-Aldrich syndrome in 24 patients from 23 unrelated Chinese families.	Zhang ZY	Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology	2010	PMID: 20546529
Characterization of Wiskott-Aldrich syndrome (WAS) mutants using Saccharomyces cerevisiae.	Rajmohan R	FEMS yeast research	2009	PMID: 19817875
Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.	Jin Y	Blood	2004	PMID: 15284122
Clinical course of patients with WASP gene mutations.	Imai K	Blood	2004	PMID: 12969986
Missense C168T in the Wiskott--Aldrich Syndrome protein gene is a common mutation in X-linked thrombocytopenia.	Ho LL	British journal of haematology	2001	PMID: 11167787
Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype.	Zhu Q	Blood	1997	PMID: 9326235
Isolated X-linked thrombocytopenia in two unrelated families is associated with point mutations in the Wiskott-Aldrich syndrome protein gene.	de Saint Basile G	The Journal of pediatrics	1996	PMID: 8757563
The mouse homolog of the Wiskott-Aldrich syndrome protein (WASP) gene is highly conserved and maps near the scurfy (sf) mutation on the X chromosome.	Derry JM	Genomics	1995	PMID: 8666397
Identification of mutations in the Wiskott-Aldrich syndrome gene and characterization of a polymorphic dinucleotide repeat at DXS6940, adjacent to the disease gene.	Kwan SP	Proceedings of the National Academy of Sciences of the United States of America	1995	PMID: 7753869
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Text-mined citations for rs132630273 ...

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Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs132630273 ...