NM_000419.5(ITGA2B):c.2602-2A>G AND Glanzmann thrombasthenia

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 7, 2023
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:: RCV001580239.5

Allele description [Variation Report for NM_000419.5(ITGA2B):c.2602-2A>G]

NM_000419.5(ITGA2B):c.2602-2A>G

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.2602-2A>G

HGVS:

NC_000017.11:g.44375718T>C
NG_008331.1:g.18788A>G
NG_136687.1:g.658T>C
NM_000419.5:c.2602-2A>GMANE SELECT
LRG_479:g.18788A>G
NC_000017.10:g.42453086T>C
NC_000017.10:g.42453086T>C
NM_000419.4:c.2602-2A>G

Links:

dbSNP: rs2143436505

NCBI 1000 Genomes Browser:

rs2143436505

Molecular consequence:

NM_000419.5:c.2602-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001809877	ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen Platelet ACMG Specifications v2-1)	Likely pathogenic (Sep 7, 2023)	germline	curation	Citation Link,
SCV004298231	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 25, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 21917754, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001809877

ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen Platelet ACMG Specifications v2-1)

Likely pathogenic
(Sep 7, 2023)

germline

curation

Citation Link,

SCV004298231

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 25, 2023)

germline

clinical testing

PubMed (3)
[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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models.

Nurden AT, Fiore M, Nurden P, Pillois X.

Blood. 2011 Dec 1;118(23):5996-6005. doi: 10.1182/blood-2011-07-365635. Epub 2011 Sep 13. Review.

PubMed [citation]

PMID:: 21917754

See all PubMed Citations (3)

Details of each submission

From ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen, SCV001809877.2

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

Description

The NM_000419.5(ITGA2B):c.2602-2A>G variant disrupts the canonical splice acceptor site in intron 25 and is predicted to result in skipping of exon 26, removing 3.9% of the protein (PVS1_moderate). The variant is absent from population database, including gnomADv2.1.1 (PM2_supporting). It is reported in one compound heterozygous individual with the c.2602-3C>A and Thr281Ile (PMID: 25373348). GT16 of PMID: 25373348 meets bleeding phenotype, aggregometry criteria, integrin expression is reported to be <5% reduced by flow cytometry, and all exons of ITGA2B and ITGB3 genes as well as surrounding intron regions were sequenced (PP4_strong). In summary, based on evidence at this time the variant is classified as likely pathogenic for GT. GT-specific criteria applied: PVS1_Moderate, PP4_Strong, PM2_Supporting.

#	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, SCV004298231.1

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1210193). This variant has not been reported in the literature in individuals affected with ITGA2B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 25 of the ITGA2B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ITGA2B are known to be pathogenic (PMID: 21917754).

#	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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