NM_000377.3(WAS):c.257G>A (p.Arg86His) AND Wiskott-Aldrich syndrome

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 29, 2024
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:: RCV000011864.13

Allele description [Variation Report for NM_000377.3(WAS):c.257G>A (p.Arg86His)]

NM_000377.3(WAS):c.257G>A (p.Arg86His)

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.257G>A (p.Arg86His)

HGVS:

NC_000023.11:g.48684407G>A
NG_007877.1:g.5611G>A
NM_000377.3:c.257G>AMANE SELECT
NP_000368.1:p.Arg86His
NP_000368.1:p.Arg86His
LRG_125t1:c.257G>A
LRG_125:g.5611G>A
LRG_125p1:p.Arg86His
NC_000023.10:g.48542796G>A
NM_000377.2:c.257G>A
P42768:p.Arg86His

Protein change:

R86H; ARG86HIS

Links:

UniProtKB: P42768#VAR_005830; OMIM: 300392.0003; dbSNP: rs132630268

NCBI 1000 Genomes Browser:

rs132630268

Molecular consequence:

NM_000377.3:c.257G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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
SCV000032097	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1996)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 8528199, 8682510
SCV000918355	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 20, 2018)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 8069912, 17213309, 18162713, 21185603, 10202051, 16638962, 8528198 Citation Link,
SCV001524706	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 5, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002500931	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	maternal, de novo	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34355501, 25741868
SCV002557408	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11242115, 12969986, 17213309, 20173115, 20513746, 21185603, 25741868
SCV004808219	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	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	unknown	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	maternal	yes	3	not provided	not provided	3	yes	clinical testing
not provided	de novo	yes	1	not provided	not provided	1	no	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

WASP gene mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia.

Derry JM, Kerns JA, Weinberg KI, Ochs HD, Volpini V, Estivill X, Walker AP, Francke U.

Hum Mol Genet. 1995 Jul;4(7):1127-35.

PubMed [citation]

PMID:: 8528199

Wiskott-Aldrich syndrome: no strict genotype-phenotype correlations but clustering of missense mutations in the amino-terminal part of the WASP gene product.

Schindelhauer D, Weiss M, Hellebrand H, Golla A, Hergersberg M, Seger R, Belohradsky BH, Meindl A.

Hum Genet. 1996 Jul;98(1):68-76.

PubMed [citation]

PMID:: 8682510

See all PubMed Citations (15)

Details of each submission

From OMIM, SCV000032097.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a patient with Wiskott-Aldrich syndrome (WAS; 301000), unrelated to the patient with the arg86-to-leu mutation (300392.0002), Derry et al. (1994) identified a G-to-A transition at nucleotide 291 changing the same arginine to a histidine. The patient's mother and maternal grandmother were heterozygous for the mutant allele. In one instance, the normal codon CGC was changed to CTC (leu); in the other instance, it was changed to CAC (his).

Schindelhauer et al. (1996) found extremely variable expression of a disease in a large Swiss family with the R86H mutation of 5 affected males. One died in infancy from infections and 2 were diagnosed as having the classic WAS phenotype. In contrast, 2 brothers had a mild phenotype with survival into adulthood and had children of their own.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918355.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: WAS c.257G>A (p.Arg86His) results in a non-conservative amino acid change located in the EVH1 domain of 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 195436 control chromosomes (gnomAD). c.257G>A has been reported in the literature in multiple individuals from different ethnicities who were affected with Wiskott-Aldrich Syndrome (e.g. Derry 1994, Kolluri 1995, Park 2007, Alapi 2006, Gulacsy 2011). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, demonstrating a disrupted interaction with WIP and a severe decrease in protein level (with normal mRNA levels) in T cells from a patient (Stewart 1999, de La Fuente 2007). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 Baylor Genetics, SCV001524706.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology, SCV002500931.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	clinical testing	PubMed (2)
2	not provided	1	not provided	yes	clinical testing	PubMed (2)
3	not provided	1	not provided	yes	clinical testing	PubMed (2)
4	not provided	1	not provided	no	clinical testing	PubMed (2)

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557408.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The 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 severe congenital neutropenia (MIM#300299; PMID: 11242115; 20513746). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Affected individuals can show marked inter-/intra-familial variability in clinical manifestations (Gene Reviews) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (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 and very highly conserved with a minor amino acid change. (SP) 0600 - Variant is located in the annotated WH1 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic (5x in ClinVar) and in at least 3 patients with Wiskott-Aldrich syndrome (PMID: 21185603). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrated the mutant protein disrupted interaction with WIP and lead to a severe decrease in protein level; (PMID: 17213309). (SP) 0703 - Multiple other missense variants comparable to the one identified in this case have previous evidence for pathogenicity. Alternative missense changes to glycine, cysteine and leucine have previously been reported in patients with WAS-related conditions (ClinVar, PMID: 21185603; 20173115). (SP) 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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004808219.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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