ClinVar

Description

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.