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

CA915940800

627292 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

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

Approved on: 2024-06-06

Published on: 2024-06-07

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

• Met criteria codes: PM2_Supporting PVS1_Strong

• Not Met criteria codes: PP4 PM3

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.2992del (p.Trp998GlyfsTer?) variant causes a frameshift and subsequent stop loss, resulting in 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 (PVS1_strong). This variant is absent from gnomAD v4.0 (PM2_Supporting). Patient TGP0655, of PMID: 31064749, is compound heterozygous for c.409-1G>A (classified Likely Pathogenic by the PD VCEP) and c.2992del, however confirmation of trans phase and sufficient phenotypic information were not available for this patient to meet any criteria. In summary, this variant is classified as uncertain significance for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PVS1_Strong, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v4.0 (PM2_Supporting).
• PVS1_Strong: The NM_000419.5(ITGA2B):c.2992del (p.Trp998GlyfsTer?) variant causes a frameshift and subsequent stop loss, resulting in 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 (PVS1_strong).

Not Met criteria codes

• 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 by immunophenotyping but no additional information was available.
• 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.