Submissions for variant NM_000419.5(ITGA2B):c.3077G>A (p.Arg1026Gln)

dbSNP: rs879255514

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001225267	SCV001397533	uncertain significance	Glanzmann thrombasthenia	2023-09-07	reviewed by expert panel	curation	The NM_000419.5:c.3077G>A variant results in the Arg1026Gln missense change. It is absent in population databases, including gnomADv2.1.1 (PM2_supporting), and is predicted damaging by in silico tools (REVEL score of 0.904; PP3). One compound heterozygous individual with mild bleeding, thrombocytopenia and platelet anisotrpy is reported in the literature several times (PMID: 25728920) with confirmation of c.1440-13_1440-1del (classified Pathogenic by the PD VCEP; PM3) in trans. The variant results in reduced expression of the αIIbβ3 complex on platelet surface. The expressed αIIbβ3 was not constitutively active and were able to bind fibrinogen only upon activation by anti-LIBS antibody. In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PM2_Supporting, PM3, PP3 (PD VCEP specifications version 2.1).
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852105	SCV000899663	uncertain significance	Thrombocytopenia	2019-02-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228135	SCV002511497	uncertain significance	not specified	2022-04-07	criteria provided, single submitter	clinical testing	Variant summary: ITGA2B c.3077G>A (p.Arg1026Gln, also known as p.Arg995Gln in literatures) results in a conservative amino acid change located in the cytoplasmic domain (Peyruchaud_1998) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Additionally, multiple structural studies showed alphaIIb R995/beta D732 salt bridge confers stability on the inactive state of integrin, supporting this residue is important for protein function (Ghevaert_2007, Yang_2009, Jayo_2010). The variant allele was found at a frequency of 4e-06 in 251278 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3077G>A has been reported in the literature in individuals affected with Glanzmann Thrombasthenia-Like Syndrome (Nurden_2015, French_1997, Peyruchaud_1998, Morais_2020). These data do not allow any conclusion about variant significance. At least one functional study reports this variant decreases surface alphaIIb -beta3 expression by approximately 50% of WT in cells and the mutated complex was not in a high activation state but remained functional in that activation could be induced by the anti-LIBS6 antibody (Peyruchaud_1998). Two ClinVar submitters (evaluation after 2014), including one expert panel (ClinGen Platelet Disorders Variant Curation Expert Panel,ClinGen), cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000043485	SCV004013100	likely pathogenic	Platelet-type bleeding disorder 16		criteria provided, single submitter	clinical testing
OMIM	RCV000043485	SCV000067297	pathogenic	Platelet-type bleeding disorder 16	2011-09-01	no assertion criteria provided	literature only