ClinVar Miner

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

dbSNP: rs766503255
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Total submissions: 14
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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
Labcorp Genetics (formerly Invitae), Labcorp 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004586035 SCV005076234 pathogenic ITGA2B-related disorder 2024-04-15 criteria provided, single submitter clinical testing Variant summary: ITGA2B c.3076C>T (p.Arg1026Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251260 control chromosomes. c.3076C>T has been reported in the literature in multiple individuals affected with macrothrombocytopenia (Kunishima_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that the variant leads to constitutive activation, membrane ruffling, abnormal cytoplasmic protrusions, and defective proplatelet formation (Kunishima_2011). In addition, knock-in mice with this variant developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation (Akuta_2020). The following publications have been ascertained in the context of this evaluation (PMID: 31691484, 21454453). In ClinVar contains an entry for this variant (Variation ID: 50233). Based on the evidence outlined above, the variant was classified as pathogenic.
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
PreventionGenetics, part of Exact Sciences RCV004586035 SCV005364525 pathogenic ITGA2B-related disorder 2024-04-17 no assertion criteria provided clinical testing The ITGA2B c.3076C>T variant is predicted to result in the amino acid substitution p.Arg1026Trp. This variant (aka R995W) has been reported in several unrelated families to be a cause of autosomal dominant macrothrombocytopenia (Kunishima et al. 2011. PubMed ID: 21454453; Khoriaty et al. 2019. PubMed ID: 31119735). Functional studies show that the p.Arg1026Trp variant causes defective platelet activation (Kunishima et al. 2011. PubMed ID: 21454453). A similar variant, p.Arg1026Gln, has also reported in an individual with Glanzmann thrombasthenia (French et al. 1997. PubMed ID: 9215749) suggesting that amino acid residue p.Arg1026 is important for proper ITGA2B function. This variant has not been reported in a large population database, indicating this variant is rare. In summary, the c.3076C>T variant is categorized as pathogenic.

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