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:c.97A>G

CA399806951

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0100326)

Inheritance Mode: Autosomal recessive inheritance

UUID: 14f93a2b-ecb8-40b1-a935-12924abcceee

Approved on: 2022-11-15

Published on: 2022-12-07

HGVS expressions

NM_000419.5:c.97A>G

NC_000017.11:g.44389377T>C

CM000679.2:g.44389377T>C

NC_000017.10:g.42466745T>C

CM000679.1:g.42466745T>C

NC_000017.9:g.39822271T>C

NG_008331.1:g.5129A>G

ENST00000262407.6:c.97A>G

ENST00000262407.5:c.97A>G

NM_000419.3:c.97A>G

NM_000419.4:c.97A>G

Pathogenic

PP4_Strong PP1_Strong PM3_Supporting PP3 PS3 PM2_Supporting

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.97A>G (p.Asn33Asp) missense variant has been reported in four homozygous siblings (patients 2, 4, 6, and 9 PMID:21029361; PM3_supporting). All siblings displayed abnormal bleeding and one sibling tested for platelet aggregation demonstrated impaired response to agonists, with a normal response to ristocetin, which is characteristic of GT. Three of the siblings, including the proband, demonstrated absent platelet αIIbβ3 surface expression measured by flow cytometry (PP4_strong, PP1_strong). In Silico predictor revealed a REVEL score of 0.773, predicting a pathogenic effect (PP3). The variant is not found in gnomAD v2.1.1 (PM2_supporting). In BHK cells transfected with the p.Asn33Asp variant, surface expression of αIIbβ3 was absent (PS3). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive Glanzmann thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PP1_strong, PP3, PS3, PM2_supporting, and PM3_supporting.

PP4_Strong

At least one patient (Patient-III2 in PMID:21029361) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was not found (<25%), as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries.

PP1_Strong

The variant has been reported to segregate with Glanzmann Thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus three affected siblings with the same homozygous genotype. (PP1_strong, PMID: 21029361).

PM3_Supporting

This variant has been detected in at least 1 proband with Glanzmann thrombasthenia. One proband was homozygous for the variant (PMID:21029361). Total points: .5 (PM3_Supporting).

PP3

The computational predictor REVEL gives a score of [.773], which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3).

PS3

Surface expression of αIIb and αIIbβ3 measured by flow cytometry in BHK cells transiently co-transfected with Asn2Asp variant αIIb and wild type β3 showed decreased expression at 0% (<5%) WT levels, indicating that this variant impacts protein function (PMID:21029361) (PS3).

PM2_Supporting

This variant is absent from gnomAD v[2.1.1] (PM2_Supporting).

Curation History

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