Submissions for variant NM_000419.5(ITGA2B):c.2965G>A (p.Ala989Thr)

gnomAD frequency: 0.00065  dbSNP: rs78165611

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001128134	SCV001397573	likely benign	Glanzmann thrombasthenia	2020-06-16	reviewed by expert panel	curation	The ITGA2B missense variant c.2965G>A (p.Ala989Thr) has been observed in at least two probands with GT (PMIDs: 25539746, 15099289) however it was in cis with the pathogenic variant Val982Met.Expression in COS-7 cells did not reduce αIIbβ3 surface expression, however functionality was not assessed. Computational evidence suggest no impact on the gene/gene product, with a REVEL score of 0.13. In summary, this variant meets criteria to be classified as Likely Benign for GT. GT-specific criteria applied: BP2 and BP4.
Illumina Laboratory Services, Illumina	RCV001128134	SCV001287541	uncertain significance	Glanzmann thrombasthenia	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001128134	SCV003254735	uncertain significance	Glanzmann thrombasthenia	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 989 of the ITGA2B protein (p.Ala989Thr). This variant is present in population databases (rs78165611, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Glanzmann thrombasthenia who also carried additional ITGA2B variants that may account for their clinical status (PMID: 15099289, 20020534, 25539746). ClinVar contains an entry for this variant (Variation ID: 417951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ITGA2B protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ITGA2B function (PMID: 15099289). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV003424041	SCV004140676	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	ITGA2B: BP4
PreventionGenetics, part of Exact Sciences	RCV003925398	SCV004746585	likely benign	ITGA2B-related condition	2022-02-01	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477811	SCV000536912	uncertain significance	Platelet-type bleeding disorder 16; Glanzmann thrombasthenia	2016-02-15	no assertion criteria provided	research