Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000419.5(ITGA2B):c.476G>T (p.Gly159Val)

CA399805900

977126 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 3cba4d4c-64ad-4e93-a2f6-e178841f7086

Approved on: 2025-05-01

Published on: 2025-05-02

HGVS expressions

NM_000419.5(ITGA2B):c.476G>T (p.Gly159Val)

NM_000419.5:c.476G>T

NC_000017.11:g.44385649C>A

CM000679.2:g.44385649C>A

NC_000017.10:g.42463017C>A

CM000679.1:g.42463017C>A

NC_000017.9:g.39818543C>A

NG_008331.1:g.8857G>T

ENST00000262407.6:c.476G>T

ENST00000262407.5:c.476G>T

ENST00000592944.1:n.161G>T

NM_000419.3:c.476G>T

NM_000419.4:c.476G>T

Likely Pathogenic

PM2_Supporting PP3 PP4_Moderate PM5_Supporting PM3_Supporting

PS3

Evidence Links 1

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2.1

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The missense variant NM_000419.5(ITGA2B):c.476G>T (p.Gly159Val) has been reported in at least one patient (P2 in PMID: 34275420) with mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). The patient is homozygous for Gly159Val (PM3_supporting). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.751, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3) and is is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant c.475G>A (p.Gly159Ser) [PMID: 16359515] in the same codon has been classified Likely Pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP (PM5_supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP3, PP4_moderate, PM2_supporting, PM3_supporting, PM5_supporting (VCEP specifications version 2.1).

PM2_Supporting

This variant is absent from gnomAD v4.1 (PM2_Supporting).

PP3

The computational predictor REVEL gives a score of 0.751, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on ITGB3 function (PP3).

PP4_Moderate

At least one patient (Patient 1 in PMID: 34275420) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Platelet surface expression of the αIIbβ3 complex was not tested by these authors though the patient was reported as type I GT from local lab in Turkey by flow cytometry analysis.

PM5_Supporting

Another missense variant c.475G>A (p.Gly159Ser) [PMID: 16359515] in the same codon has been classified Likely Pathogenic for Glanzmann thrombasthenia by the ClinGen PD VCEP.

PM3_Supporting

P2 (PMID: 34275420) is homozygous for this variant (PM3_supporting).

PS3

Surface expression of αIIbβ3 measured by flow cytometry in COS-7 cells transiently co-transfected with Gly159Val variant αIIb and wild type β3 showed normal expression levels (PS3_NotMet). Testing of fibrinogen binding function of the expressed protein was not reported. The authors suggest that the c.476G>T variant may instead affect splicing; and report that the Human Splice Finder tool predicted that the αIIb:c.476 G > T SNV might create a cryptic donor splicing site in exon 4 leading to a frame shift (αIIb:p.Gly159Alafs). This splice impact is not predicted by SpliceAI and was not confirmed in patient cDNA or mini-gene assay. PubMed:34275420

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.