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.2992del (p.Trp998fs)

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CA915940800

627292 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann's thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 8a713b8e-9594-44d5-96a2-124c9e009890

Approved on: 2021-05-07

Published on: 2021-08-20

HGVS expressions

NM_000419.5:c.2992del

NM_000419.5(ITGA2B):c.2992del (p.Trp998fs)

NC_000017.11:g.44374422del

CM000679.2:g.44374422del

NC_000017.10:g.42451790del

CM000679.1:g.42451790del

NC_000017.9:g.39807316del

NG_008331.1:g.20084del

ENST00000262407.6:c.2992del

ENST00000648408.1:c.2374+237del

ENST00000262407.5:c.2992del

ENST00000587295.5:c.253+1411del

ENST00000588098.1:c.37+237del

ENST00000592462.5:n.2691del

NM_000419.3:c.2992del

NM_000419.4:c.2992del

Uncertain Significance

PM2_Supporting PVS1_Strong

PM3 PP4

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 NM_000419.5(ITGA2B):c.2992del variant that results in the p.Trp998Glyfs frameshift has been reported in at least one GT patient with the c.409-1G>A variant in trans (PMID: 22190468). The variant causes stop loss and the addition of 90 amino acids to the ITGA2B protein, which alters the transmembrane domain. The variant is absent from population databases. In summary, based on the available evidence at this time, the variant is classified as uncertain significance due to insufficient evidence. GT-specific criteria applied: PVS1_Strong, PM2_Supporting.

PM2_Supporting

This variant is absent from all population cohorts in gnomAD, ExAC, 1000 Genomes, and ESP.

PVS1_Strong

The c.2992del variant causes a frameshift and subsequent stop loss, p.Trp998GlyfsTer?. This results alteration of the remaining 42 amino acids followed by the addition of 90 amino acids to the ITGA2B protein. This alters the transmembrane domain of the protein which is considered a critical region for protein function by the Platelet Disorders VCEP. Per the SVI PVS1 decision tree, PVS1_Strong is applied.

PM3

Patient TGP0655, of PMID: 31064749, is compound heterozygous for c.409-1G>A (Likely Pathogenic) and c.2992del. Confirmation of trans phase not reported.

PP4

Patient TGP0655, of PMID: 31064749, is stated to have a disease of platelet function (reported in ClinVar as Glanzmann thrombasthenia). Personal communication with authors confirmed that the patient was diagnosed with Glanzmann thrombasthenia with immunophenotyping.

Curation History

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