Variant: NM_000419.5(ITGA2B):c.2965del (p.Ala989fs)

CA913189248

953057 (ClinVar)

Gene: ITGA2B

Condition: Glanzmann thrombasthenia

Inheritance Mode: Autosomal recessive inheritance

UUID: 8f73c6f5-d08e-48a2-904d-132622b09984

Approved on: 2024-05-02

Published on: 2024-05-03

HGVS expressions

NM_000419.5:c.2965del
NM_000419.5:c.2965delG
NM_000419.5(ITGA2B):c.2965del (p.Ala989fs)
NC_000017.11:g.44374451del
CM000679.2:g.44374451del
NC_000017.10:g.42451819del
CM000679.1:g.42451819del
NC_000017.9:g.39807345del
NG_008331.1:g.20057del
ENST00000262407.6:c.2965del
ENST00000648408.1:c.2374+210del
ENST00000262407.5:c.2965del
ENST00000587295.5:c.253+1384del
ENST00000588098.1:c.37+210del
ENST00000592462.5:n.2664del
NM_000419.3:c.2965del
NM_000419.4:c.2965del

Pathogenic

• Met criteria codes: PM2_Supporting PM3_Strong PVS1_Strong PP4_Moderate

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.2965del (p.Ala989Profs) variant has been described in at least three patients with phenotypes highly specific to GT including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3 (PMIDs: 25539746, 28983057; PP4_moderate). It was reported twice in the homozygous state (PMIDs: 25539746, 28983057) and once in a compound heterozygote (PMID: 28983057) with Val982Met (classified as Pathogenic by the ClinGen Platelet Disorders VCEP) (PM3_strong). This frameshift variant occurs in exon 28 and results in 51 altered amino acids followed by as stop loss and the elongation of the protein by 90 amino acids, which alters the entirety of the transmembrane domain which is critical to protein function (PMID: 25617834) as well as the cytoplasmic domain (PVS1_Strong). The variant is absent from population databases including gnomADv2.1.1 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PM2_supporting, PVS1_strong, PM3_strong, PP4_moderate. (PD-VCEP specifications v2.1)

Met criteria codes

• PM2_Supporting: This variant is absent from gnomADv2.1.1 (PM2_supporting).
• PM3_Strong: This variant has been reported twice in the homozygous state (1pt) and once in a compound heterozygote with Val982Met (classified as Pathogenic by the ClinGen Platelet Disorders VCEP) and the trans phase was confirmed (1pt). Total 2pt (PM3_Strong)
• PVS1_Strong: The c.2965del variant occurs in exon 28 of 30 but does not generate a new stop codon prior to the original site. Instead it would result in 51 altered amino acids, starting from Ala989Pro, followed by as stop loss and the elongation of the protein by 90 amino acids until a new stop codon is reached. This alters the entirety of the transmembrane domain which is critical to protein function (PMID: 25617834) as well as the cytoplasmic domain.
• PP4_Moderate: Two probands have been described in PMIDs 25539746 (GT-8) and 28983057 (Case 37) with phenotypes which meet the criteria for PP4_moderate; including mucocutaneous bleeding, impaired aggregation with all agonists except ristocetin, and reduced surface expression of αIIbβ3.