NM_000377.3(WAS):c.809T>C (p.Leu270Pro) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 29, 2021
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:: RCV001851800.4

Allele description [Variation Report for NM_000377.3(WAS):c.809T>C (p.Leu270Pro)]

NM_000377.3(WAS):c.809T>C (p.Leu270Pro)

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.809T>C (p.Leu270Pro)

HGVS:

NC_000023.11:g.48688331T>C
NG_007877.1:g.9535T>C
NM_000377.3:c.809T>CMANE SELECT
NP_000368.1:p.Leu270Pro
LRG_125:g.9535T>C
NC_000023.10:g.48546720T>C
P42768:p.Leu270Pro

Protein change:

L270P; LEU270PRO

Links:

UniProtKB: P42768#VAR_033256; OMIM: 300392.0012; dbSNP: rs132630274

NCBI 1000 Genomes Browser:

rs132630274

Molecular consequence:

NM_000377.3:c.809T>C - 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
SCV002225495	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 29, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20513746, 24402308, 29078804, 11242115, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002225495

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 29, 2021)

germline

clinical testing

PubMed (5)
[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

Activating WASP mutations associated with X-linked neutropenia result in enhanced actin polymerization, altered cytoskeletal responses, and genomic instability in lymphocytes.

Westerberg LS, Meelu P, Baptista M, Eston MA, Adamovich DA, Cotta-de-Almeida V, Seed B, Rosen MK, Vandenberghe P, Thrasher AJ, Klein C, Alt FW, Snapper SB.

J Exp Med. 2010 Jun 7;207(6):1145-52. doi: 10.1084/jem.20091245. Epub 2010 May 31.

PubMed [citation]

PMID:: 20513746
PMCID:: PMC2882832

The open conformation of WASP regulates its nuclear localization and gene transcription in myeloid cells.

Looi CY, Sasahara Y, Watanabe Y, Satoh M, Hakozaki I, Uchiyama M, Wong WF, Du W, Uchiyama T, Kumaki S, Tsuchiya S, Kure S.

Int Immunol. 2014 Jun;26(6):341-52. doi: 10.1093/intimm/dxt072. Epub 2014 Jan 8.

PubMed [citation]

PMID:: 24402308

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002225495.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects WAS function (PMID: 11242115, 20513746, 24402308, 29078804). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 11125). This missense change has been observed in individual(s) with WAS-related conditions (PMID: 11242115). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 270 of the WAS protein (p.Leu270Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline.

#	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: Sep 29, 2024

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