Variant: NM_000419.5:c.3062T>C

CA399787956

1330348 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 2a4ec01d-f6e0-49d6-8cd4-1db73b8e4a7f

Approved on: 2024-10-15

Published on: 2024-10-16

HGVS expressions

NM_000419.5:c.3062T>C
NC_000017.11:g.44372422A>G
CM000679.2:g.44372422A>G
NC_000017.10:g.42449790A>G
CM000679.1:g.42449790A>G
NC_000017.9:g.39805316A>G
NG_008331.1:g.22084T>C
ENST00000262407.6:c.3062T>C
ENST00000648408.1:c.2376T>C
ENST00000262407.5:c.3062T>C
ENST00000587295.5:c.255T>C
ENST00000588098.1:c.39T>C
NM_000419.3:c.3062T>C
NM_000419.4:c.3062T>C

Uncertain Significance

• Met criteria codes: PP4_Strong PM3_Supporting PM2_Supporting BP4

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

Evidence submitted by expert panel

Platelet Disorders VCEP

The NM_000419.5(ITGA2B):c.3062T>C (p.Val1021Ala) missense variant has been reported in at least two Glanzmann thrombasthenia patients (PMID: 21113249). Patient SB displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 23%, as measured by flow cytometry, and there was 12-13% binding to PAC-1. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong; PMID: 21113249). Patient LN is homozygous for c.3062T>C (PM3_supporting; PMID: 21113249). This variant is absent from gnomAD v4.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.084, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, and BP4. (VCEP specifications version 2).

Met criteria codes

• PP4_Strong: Patient SB displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to 23%, as measured by flow cytometry, and there was 12-13% binding to PAC-1. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong; PMID: 21113249).
• PM3_Supporting: Patient LN is homozygous for c.3062T>C 0.5pt (PM3_supporting; PMID: 21113249).
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).
• BP4: The computational predictor REVEL gives a score of 0.084, which is below the ClinGen PD VCEP threshold of <0.25 and predicts no damaging effect on ITGA2 function (BP4). And the computational splicing predictors SpliceAI, HSF, MaxEntScan, and varSEAK indicated that the variant has no impact on splicing.