Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
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, |
RCV000851592 | SCV000899328 | pathogenic | Thrombocytopenia | 2019-02-01 | criteria provided, single submitter | research | |
Labcorp Genetics |
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, |
RCV001818214 | SCV002072183 | pathogenic | not provided | 2017-09-15 | criteria provided, single submitter | clinical testing | |
ISTH- |
RCV000043486 | SCV002500889 | likely pathogenic | Platelet-type bleeding disorder 16 | criteria provided, single submitter | clinical testing | ||
Wangler Lab, |
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, |
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, |
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, |
RCV000043486 | SCV001190807 | pathogenic | Platelet-type bleeding disorder 16 | 2020-02-05 | no assertion criteria provided | clinical testing | |
Prevention |
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. |