Submissions for variant NM_000419.5(ITGA2B):c.59T>G (p.Leu20Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002511150	SCV002820943	likely pathogenic	Glanzmann thrombasthenia	2022-03-07	reviewed by expert panel	curation	The NM_000419.5:c.59T>G variant in ITGA2B is a missense variant predicted to cause substitution of leucine by arginine at amino acid 20 (p.Leu20Arg). This variant has been observed in homozygosity 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) (PM3_Supporting). This individual displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <5%, 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). Furthermore, the computational predictor REVEL gives a score of 0.772, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). 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: PM2_Supporting, PM3_Supporting, PP3, PP4_Strong. (VCEP specifications version 2; date of approval 2/3/2022)
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002281028	SCV002569357	uncertain significance	Glanzmann thrombasthenia 1		criteria provided, single submitter	clinical testing