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.693dup

CA915940315

Gene: ITGA2B (HGNC:3674)

Condition: Glanzmann's thrombasthenia (MONDO:0010119)

Inheritance Mode: Autosomal recessive inheritance

UUID: 2dce6c82-b717-4714-a586-2af41e85c7d6

Approved on: 2020-12-02

Published on: 2021-01-22

HGVS expressions

NM_000419.5:c.693dup

NM_000419.3:c.693dup

NM_000419.4:c.693dup

ENST00000262407.5:c.693dup

ENST00000589645.5:n.144dup

ENST00000591990.5:n.55dup

ENST00000592075.5:n.62dup

ENST00000592226.5:n.39+110dup

ENST00000592253.5:n.201dup

ENST00000592944.1:n.375dup

NC_000017.11:g.44385055dup

CM000679.2:g.44385055dup

NC_000017.10:g.42462423dup

CM000679.1:g.42462423dup

NC_000017.9:g.39817949dup

NG_008331.1:g.9452dup

Pathogenic

PM3 PVS1 PP4_Strong PM2_Supporting

Evidence Links 0

Expert Panel

Platelet Disorders VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Platelet Disorders VCEP

The ITGA2B frameshift variant NM_000419.5:c.693dup (p.Ala232CysfsTer24) is expected to introduce a premature termination codon 24 amino acids downstream and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in two individuals with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT-9, PMID: 25539746 and Patient ZM, PMID: 12083483). Furthermore, this variant is absent from population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM3, PP4_strong, PM2_supporting.

PM3

This variant has been observed in homozygosity in two individuals (GT-9, PMID: 25539746 and Patient ZM, PMID: 12083483), sufficient to apply PM3.

PVS1

This variant introduces a frameshift in exon 7/30 resulting in a premature termination codon 24 amino acids downstream. The resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function.

PP4_Strong

This variant was reported in homozygosity in two individuals (GT-9, PMID: 25539746 and Patient ZM, PMID: 12083483). At least one of these individuals (Patient ZM, PMID: 12083483) meets all requirements for PP4 at an upgraded strength of strong (PP4_strong): epistaxis; absent platelet aggregation in response to physiologic agonists except normal response to ristocetin; flow cytometry showed trace expression of αIIb; direct sequencing of all exons and intron/exon boundaries of ITGA2B and ITGB3.

PM2_Supporting

This is a rare variant not reported in control population databases, including gnomAD v2.1.1, gnomAD v3, PAGE, 1000 Genomes, and ESP, meeting the criterion to apply PM2_supporting.

Curation History

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