Submissions for variant NM_000419.5(ITGA2B):c.1772A>C (p.Asp591Ala)

gnomAD frequency: 0.00001  dbSNP: rs778608263

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV000851720	SCV005061675	pathogenic	Glanzmann thrombasthenia	2024-04-16	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.1772A>C (p.Asp591Ala) missense variant has been reported in at least six patients, including at least one patient (P13 in PMID: 34275420) who 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 (PP4_strong). At least four patients have been reported homozygous for this variant (PMIDs: 34275420, 29385657, ClinVar SCV004013075.1). Two additional compound heterozygous patients have been reported (PMID: 34355501), the first patient had Pro176Ala confirmed in trans (classified Pathogenic by the PD-EP, score 1pt) and the second patient had c.1440-13_1440-1del assumed in trans (PM3_strong).The highest population minor allele frequency in gnomAD v4.0.0 is 0.000005932 (7/1180006 alleles) in the European (non-Finnish) population, which is lower than the ClinGen PD VCEP threshold (<0.0001; PM2_Supporting). The computational predictor REVEL gives a score of 0.755, which is above the ClinGen PD VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets criteria to be classified as Pathogenic for autosomal recessive Glanzmann thrombasthenia. GT-specific criteria applied: PM2_supporting, PM3_strong, PP4_strong and PP3.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851720	SCV000899555	likely pathogenic	Glanzmann thrombasthenia	2019-02-01	criteria provided, single submitter	research
Departement d'Immunology Plaquettaire, Institut National de la Transfusion Sanguine	RCV000851720	SCV001430685	likely pathogenic	Glanzmann thrombasthenia		criteria provided, single submitter	provider interpretation	The variant alters the expression of the platelets fibrinogen receptor alphaIIb beta3
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268765	SCV001447937	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002222626	SCV002500888	likely pathogenic	Platelet-type bleeding disorder 16		criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003313788	SCV004013075	likely pathogenic	Glanzmann thrombasthenia 1		criteria provided, single submitter	clinical testing