Submissions for variant NM_000419.5(ITGA2B):c.1752+2T>C

gnomAD frequency: 0.00001  dbSNP: rs769156315

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001254665	SCV001809919	pathogenic	Glanzmann thrombasthenia	2022-06-08	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.1752+2T>C splice variant is predicted to cause skipping of exon 17, introducing a premature termination codon, and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in two individuals reported to have Glanzmann's thrombasthenia (GT), however sufficient phenotype information was not provided to determine if the individual's phenotype is specific for GT. This variant is at an extremely low population frequency with an overall allele frequency from gnomAD of 0.000003988 and MAF of 0.000008834 in the non-Finnish European population. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PVS1, PM2_Supporting, and PM3.
Departement d'Immunology Plaquettaire, Institut National de la Transfusion Sanguine	RCV001254665	SCV001430684	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	RCV001268766	SCV001447938	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003339566	SCV004048507	pathogenic	Glanzmann thrombasthenia 1		criteria provided, single submitter	clinical testing	The splice variant c.1752+2T>C in ITGA2B gene is predicted to cause skipping of exon 17, introducing a premature termination codon, and the resulting mRNA product is predicted to undergo nonsense mediated decay, leading to loss of normal protein function. This variant has been observed in homozygosity in two individuals reported to have Glanzmann's thrombasthenia (Nurden AT), however sufficient phenotype information was not provided to determine if the individual's phenotype is specific for GT. The variant is reported with the allele frequency of 0.0003988% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as pathogenic. The nucleotide change in ITGA2B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as pathogenic.
Invitae	RCV001254665	SCV004298233	pathogenic	Glanzmann thrombasthenia	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 17 of the ITGA2B gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ITGA2B are known to be pathogenic (PMID: 21917754). This variant is present in population databases (rs769156315, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with autosomal recessive Glanzmann thrombasthenia (PMID: 21113249, 32089034). This variant is also known as 1754T‚ÜíC . ClinVar contains an entry for this variant (Variation ID: 977128). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.