Submissions for variant NM_000419.5(ITGA2B):c.2150T>C (p.Leu717Pro)

dbSNP: rs2143447451

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002254812	SCV002525903	likely pathogenic	Glanzmann thrombasthenia	2022-04-13	reviewed by expert panel	curation	The NM_000419.5:c.2150T>C variant in ITGA2B is a missense variant predicted to cause substitution of leucine by proline at amino acid 717 (p.Leu717Pro). This variant has been observed in compound heterozygosity in one individual (reported via personal communication with Dr. Jose Rivera, Servicio de Hematolog_x0019_ıa y Oncolog_x0019_ıa Me_x0019_dica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonacio_x0019_n, Universidad de Murcia) in combination with ITGA2B variant c.337C>T (p.Gln113Ter, classified as pathogenic by the Platelet Disorders VCEP, trans phase not confirmed) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, alphaIIbbeta3 surface expression was absent, as measured by flow cytometry and Western blot, and ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_Strong, PM2_Supporting, PM3_Supporting. (VCEP specifications version 2; date of approval 03/15/2022)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280917	SCV002569353	uncertain significance	Glanzmann thrombasthenia 1		criteria provided, single submitter	clinical testing