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.857T>A (p.Val286Asp)

CA399805011

1210210 (ClinVar)

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 5289ffc6-3f4b-45c1-b8b2-471eff1a1312

Approved on: 2023-11-02

Published on: 2023-11-03

HGVS expressions

NM_000419.5(ITGA2B):c.857T>A (p.Val286Asp)

NM_000419.5:c.857T>A

NC_000017.11:g.44384345A>T

CM000679.2:g.44384345A>T

NC_000017.10:g.42461713A>T

CM000679.1:g.42461713A>T

NC_000017.9:g.39817239A>T

NG_008331.1:g.10161T>A

ENST00000262407.6:c.857T>A

ENST00000648408.1:c.288T>A

ENST00000262407.5:c.857T>A

ENST00000589645.5:n.308T>A

ENST00000591990.5:n.402T>A

ENST00000592075.5:n.226T>A

ENST00000592226.5:n.97T>A

ENST00000592253.5:n.365T>A

ENST00000592944.1:n.539T>A

NM_000419.3:c.857T>A

NM_000419.4:c.857T>A

Likely Pathogenic

PP4_Strong PP1 PP3 PM3_Supporting 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.857T>A (p.Val286Asp) missense variant is absent from large population databases, including gnomADv2.1.1 (PM2_supporting). This variant has been reported in the homozygous state (PM3_supporting) in at least one proband who meets criteria for the GT phenotype, which includes history of significant mucocutaneous bleeding, absent platelet aggregation with three physiological agonists, normal with ristocetin. Flow cytometry demonstrated reduced (<5%) αIIbβ3 surface expression (PMID: 25728920; PP4_strong). The variant segregated with disease in two homozygous siblings (PMID: 36672149; PP1). In silico tools (REVEL score = 0.825) predict deleterious effects on gene function (PP3). In summary, this variant meets criteria for PP4_strong, PM2_supporting, PP3, PP1 and PM3_supporting; and is therefore classified as Likely Pathogenic for GT.

PP4_Strong

The p.Val286Asp variant has been reported in at least one proband who meets GT specific criteria for PP4_strong - which includes history of significant mucocutaneous bleeding, absent platelet aggregation with three physiological agonists, normal with ristocetin. Flowcytometry demonstrated reduced (<5%) αIIbβ3 surface expression. Sanger sequencing was performed to ensure coverage of all exons and UTRs of ITGA2B and ITGB3 genes.

PP1

The variant segregated with disease in two homozygous siblings (PMID: 36672149; PP1)

PP3

REVEL score=0.825, which is above the threshold of >0.70 for PP3_supporting.

PM3_Supporting

The p.Val286Asp variant has been reported in homozygous state in one proband by PMID:25728920 [0.5 points]

PM2_Supporting

p.Val286Asp is absent from large population cohorts (gnomAD).

Curation History

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