NM_000419.5(ITGA2B):c.2965G>A (p.Ala989Thr) AND Glanzmann thrombasthenia

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Jun 16, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001128134.9

Allele description [Variation Report for NM_000419.5(ITGA2B):c.2965G>A (p.Ala989Thr)]

NM_000419.5(ITGA2B):c.2965G>A (p.Ala989Thr)

Gene:

ITGA2B:integrin subunit alpha 2b [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.31

Genomic location:

Preferred name:

NM_000419.5(ITGA2B):c.2965G>A (p.Ala989Thr)

HGVS:

NC_000017.11:g.44374449C>T
NG_008331.1:g.20057G>A
NM_000419.4:c.2965G>A
NM_000419.5:c.2965G>AMANE SELECT
NP_000410.2:p.Ala989Thr
LRG_479t1:c.2965G>A
LRG_479:g.20057G>A
NC_000017.10:g.42451817C>T
NC_000017.10:g.42451817C>T
NM_000419.3:c.2965G>A
NM_000419.4(ITGA2B):c.2965G>A
p.Ala989Thr

Protein change:

A989T

Links:

dbSNP: rs78165611

NCBI 1000 Genomes Browser:

rs78165611

Molecular consequence:

NM_000419.5:c.2965G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glanzmann thrombasthenia
Synonyms:: PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY; Thrombasthenia of Glanzmann and Naegeli; Glanzmann thrombasthenia type A; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0100326; MedGen: C0040015; Orphanet: 849; OMIM: PS273800

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Escherichia coli strain Past_Mal_4 contig_5, whole genome shotgun sequence
Escherichia coli strain Past_Mal_4 contig_5, whole genome shotgun sequence
gi|2776431965|ref|NZ_JBFOBX01000000 gnl|WGS:NZ_JBFOBX01|contig_5

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001287541	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25539746, 15099289, 20020534 Citation Link,
SCV001397573	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen Platelet ACMG Specifications v2)	Likely benign (Jun 16, 2020)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 25539746, 15099289 Citation Link,
SCV003254735	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 26, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 20020534, 25539746, 15099289, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001287541

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001397573

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen Platelet ACMG Specifications v2)

Likely benign
(Jun 16, 2020)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV003254735

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 26, 2024)

germline

clinical testing

PubMed (4)
[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, curation

Citations

PubMed

AlphaIIbbeta3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function.

Jallu V, Dusseaux M, Panzer S, Torchet MF, Hezard N, Goudemand J, de Brevern AG, Kaplan C.

Hum Mutat. 2010 Mar;31(3):237-46. doi: 10.1002/humu.21179.

PubMed [citation]

PMID:: 20020534

Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study.

Sánchez-Guiu I, Antón AI, Padilla J, Velasco F, Lucia JF, Lozano M, Cid AR, Sevivas T, Lopez-Fernandez MF, Vicente V, González-Manchón C, Rivera J, Lozano ML.

Orphanet J Rare Dis. 2014 Dec 24;9:213. doi: 10.1186/s13023-014-0213-6.

PubMed [citation]

PMID:: 25539746
PMCID:: PMC4302577

See all PubMed Citations (4)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001287541.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen, SCV001397573.2

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

Description

The ITGA2B missense variant c.2965G>A (p.Ala989Thr) has been observed in at least two probands with GT (PMIDs: 25539746, 15099289) however it was in cis with the pathogenic variant Val982Met.Expression in COS-7 cells did not reduce Î±IIbÎ²3 surface expression, however functionality was not assessed. Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.13. In summary, this variant meets criteria to be classified as Likely Benign for GT. GT-specific criteria applied: BP2 and BP4.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003254735.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 989 of the ITGA2B protein (p.Ala989Thr). This variant is present in population databases (rs78165611, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Glanzmann thrombasthenia who also carried additional ITGA2B variants that may account for their clinical status (PMID: 15099289, 20020534, 25539746). ClinVar contains an entry for this variant (Variation ID: 417951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITGA2B protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ITGA2B function (PMID: 15099289). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Oct 13, 2024

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