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.3062T>C

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA399787956

1330348 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

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

PM2_Supporting BP4 PM3_Supporting PP4_Strong

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

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).

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.

PM3_Supporting

Patient LN is homozygous for c.3062T>C 0.5pt (PM3_supporting; PMID: 21113249).

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).

Curation History

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