NM_000377.3(WAS):c.881T>C (p.Ile294Thr) AND X-linked severe congenital neutropenia

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jul 17, 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:: RCV000022859.9

Allele description [Variation Report for NM_000377.3(WAS):c.881T>C (p.Ile294Thr)]

NM_000377.3(WAS):c.881T>C (p.Ile294Thr)

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.881T>C (p.Ile294Thr)

HGVS:

NC_000023.11:g.48688403T>C
NG_007877.1:g.9607T>C
NM_000377.3:c.881T>CMANE SELECT
NP_000368.1:p.Ile294Thr
NP_000368.1:p.Ile294Thr
LRG_125t1:c.881T>C
LRG_125:g.9607T>C
LRG_125p1:p.Ile294Thr
NC_000023.10:g.48546792T>C
NM_000377.2:c.881T>C

Protein change:

I294T; ILE294THR

Links:

OMIM: 300392.0025; dbSNP: rs387906717

NCBI 1000 Genomes Browser:

rs387906717

Molecular consequence:

NM_000377.3:c.881T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000044150	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 2009)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 16804117, 3284030, 19006568
SCV001141855	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002073915	Genomics Facility, Ludwig-Maximilians-Universität München	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25741868, 11242115, 19006568
SCV003845967	Lifecell International Pvt. Ltd	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19006568, 25741868
SCV005086454	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11242115, 12969986, 16804117, 20301357, 20513746, 23689198, 35404999, 25741868

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Asian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Congenital neutropenia and low serum immunoglobulin A: description and investigation of a large kindred.

Cryan EF, Deasy PF, Buckley RJ, Greally JF.

Thymus. 1988;11(3):185-99.

PubMed [citation]

PMID:: 3284030

A large kindred with X-linked neutropenia with an I294T mutation of the Wiskott-Aldrich syndrome gene.

Beel K, Cotter MM, Blatny J, Bond J, Lucas G, Green F, Vanduppen V, Leung DW, Rooney S, Smith OP, Rosen MK, Vandenberghe P.

Br J Haematol. 2009 Jan;144(1):120-6. doi: 10.1111/j.1365-2141.2008.07416.x. Epub 2008 Nov 1.

PubMed [citation]

PMID:: 19006568
PMCID:: PMC3125974

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000044150.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a boy of Zairian parentage with severe congenital neutropenia (SCNX; 300299), Ancliff et al. (2006) identified a T-to-C transition in the WAS gene, resulting in an ile294-to-thr (I294T) substitution in the GTPase-binding domain. The mutation was not detected in 100 randomly chosen controls or in 100 individuals of African origin. The X-chromosome inactivation pattern of his carrier mother showed a mean ratio of 79%:21% (wildtype:mutant alleles), with no significant differences between the inactivation pattern in purified neutrophils and CD3(+) cells. Functional analysis revealed that the I294T mutation resulted in increased WAS activity and produced marked abnormalities of cytoskeletal structure and dynamics.

In affected males and carrier females from a large Irish kindred segregating X-linked congenital neutropenia, originally reported by Cryan et al. (1988), Beel et al. (2008) identified an 882T-C transition in exon 9 of the WAS gene, resulting in the I294T mutation. Functional analysis confirmed that the I294T mutant is constitutively active toward actin polymerization. Four of 6 female carriers showed random X-chromosome inactivation. Two female carriers showed no consistent pattern of asymmetric X-chromosome inactivation.

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

From Mendelics, SCV001141855.1

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

From Genomics Facility, Ludwig-Maximilians-Universität München, SCV002073915.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

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

From Lifecell International Pvt. Ltd, SCV003845967.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Asian	1	not provided	not provided	clinical testing	PubMed (2)

Description

A Hemizygote Missense variant c.881T>C in Exon 9 of the WAS gene that results in the amino acid substitution p.Ile294Thr was identified. The observed variant has a minor allele frequency of 0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/Likely Pathogenic (Variant ID: 29967). This variant has previously been reported for X-linked neutropenia by Beel K, et,al.,2008. Functional studies also demonstrated that the p.Ile294Thr substitution affects the normal function of the WAS protein (Beel K,et,al.,2008). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

#	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		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086454.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with diseases. Loss of function is a known mechanism associated with X-linked thrombocytopenia (XLT; MIM#313900) and Wiskott-Aldrich syndrome (WAS; MIM#301000) (PMID: 12969986). While gain of function is shown to be associated with X-linked severe congenital neutropenia (MIM#300299) (PMIDs: 11242115, 20513746). (I) 0109 - This gene is associated with X-linked recessive disease. Most female heterozygotes are asymptomatic; however, skewed X-inactivation has been reported in some affected females (OMIM, PMIDs: 20301357, 23689198). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable expressivity of clinical findings and disease severity have been reported (PMID: 20301357). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated GTPase binding domain (PMID: 16804117). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic/likely pathogenic by multiple clinical testing laboratories (ClinVar). It has also been reported in multiple individuals with neutropenia (ClinVar, PMIDs: 35404999, 16804117). In one of those reported families, affected individuals have neutropenia, macrothrombocytopenia and renal failure, and there are three affected females who are heterozygous for this variant (PMID: 35404999). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant protein expressed in vitro showed an increased capacity to stimulate actin polymerisation (PMID: 16804117). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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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