Submissions for variant NM_000419.5(ITGA2B):c.3076C>T (p.Arg1026Trp)

dbSNP: rs766503255

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV001003530	SCV001397532	uncertain significance	Glanzmann thrombasthenia	2020-06-16	reviewed by expert panel	curation	The NM_000419.5:c.3076C>T variant results in the Arg1026Trp missense change. It is absent in population databases and is predicted damaging by in silico tools (REVEL score of 0.897). All the individuals with this variant, reported in the literature, are heterozygous and have macrothrombocytopenia with or without a mild bleeding tendency (PMID: 31119735, 21454453, 31064749). In summary, there is insufficient evidence at this time to classify the Arg1026Trp variant. GT-specific criteria applied: PM2_Supporting, PP3.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851592	SCV000899328	pathogenic	Thrombocytopenia	2019-02-01	criteria provided, single submitter	research
Invitae	RCV001003530	SCV001230135	pathogenic	Glanzmann thrombasthenia	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1026 of the ITGA2B protein (p.Arg1026Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant thrombocytopenia (PMID: 21454453, 29090484, 31119735). It has also been observed to segregate with disease in related individuals. This variant is also known as p.R995W. ClinVar contains an entry for this variant (Variation ID: 50233). 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 expected to disrupt ITGA2B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ITGA2B function (PMID: 21454453). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001003530	SCV001530357	pathogenic	Glanzmann thrombasthenia	2018-11-23	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing in multiple individuals [PMID 21454453, 29090484]
Genetic Services Laboratory, University of Chicago	RCV001818214	SCV002072183	pathogenic	not provided	2017-09-15	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000043486	SCV002500889	likely pathogenic	Platelet-type bleeding disorder 16		criteria provided, single submitter	clinical testing
Wangler Lab, Baylor College of Medicine	RCV000043486	SCV002577609	pathogenic	Platelet-type bleeding disorder 16		criteria provided, single submitter	clinical testing	This missense ITGA2B variant at c.3076C>T (p.R1026W) was discovered on exome through the Texome Project (R01HG011795). It is reported in the heterozygous state in individuals with ITGA2B-related disorders including autosomal dominant macrothrombocytopenia and autosomal dominant thrombocytopenia with normal platelet size (PMID: 21454453, 29090484, 31064749, 31119735, 32581362). Functional studies suggest this variant is functionally defective (PMID: 21454453, 31691484) (PS3). This variant has not been observed in gnomAD (PM2) and is predicted to be deleterious by multiple computational models (CADD:25.200) (PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic.
Baylor Genetics	RCV000043486	SCV003835333	pathogenic	Platelet-type bleeding disorder 16	2022-07-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147330	SCV003835421	pathogenic	Glanzmann thrombasthenia 1	2022-07-28	criteria provided, single submitter	clinical testing
OMIM	RCV000043486	SCV000067298	pathogenic	Platelet-type bleeding disorder 16	2011-05-19	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851592	SCV001161856	pathogenic	Thrombocytopenia	2019-09-01	no assertion criteria provided	research	The clinical significance is unchnaged from the previous submission.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000043486	SCV001190807	pathogenic	Platelet-type bleeding disorder 16	2020-02-05	no assertion criteria provided	clinical testing