17-44372408-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10575573/MONDO:0010119/011
Frequency
Consequence
NM_000419.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ITGA2B | NM_000419.5 | c.3076C>T | p.Arg1026Trp | missense_variant | 30/30 | ENST00000262407.6 | |
ITGA2B | XM_011524749.2 | c.3127C>T | p.Arg1043Trp | missense_variant | 29/29 | ||
ITGA2B | XM_011524750.2 | c.3112C>T | p.Arg1038Trp | missense_variant | 29/29 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ITGA2B | ENST00000262407.6 | c.3076C>T | p.Arg1026Trp | missense_variant | 30/30 | 1 | NM_000419.5 | P1 | |
ITGA2B | ENST00000648408.1 | c.2392C>T | p.Arg798Trp | missense_variant | 25/25 | ||||
ITGA2B | ENST00000587295.5 | c.271C>T | p.Arg91Trp | missense_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461852Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727228
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Platelet-type bleeding disorder 16 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Wangler Lab, Baylor College of Medicine | - | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 28, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Feb 05, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 19, 2011 | - - |
Glanzmann thrombasthenia Pathogenic:2Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen | Jun 16, 2020 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 23, 2018 | 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] - |
Thrombocytopenia Pathogenic:2
Pathogenic, criteria provided, single submitter | research | NIHR Bioresource Rare Diseases, University of Cambridge | Feb 01, 2019 | - - |
Pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Sep 01, 2019 | The clinical significance is unchnaged from the previous submission. - |
ITGA2B-related disorder Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 17, 2024 | 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2024 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 15, 2017 | - - |
Glanzmann thrombasthenia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 28, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at