Submissions for variant NM_000419.5(ITGA2B):c.2965del (p.Ala989fs)

dbSNP: rs2048521625

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001225294	SCV001397572	pathogenic	Glanzmann thrombasthenia	2024-05-02	reviewed by expert panel	curation	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)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002222679	SCV002500887	pathogenic	Glanzmann thrombasthenia 1		criteria provided, single submitter	clinical testing