Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV002511547 | SCV002820944 | uncertain significance | Glanzmann thrombasthenia | 2024-04-16 | reviewed by expert panel | curation | The NM_000419.5:c.1139G>A variant in ITGA2B is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 380 (p.Gly380Asp). At least one patient (Patient GM in PMID: 12083483) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, αIIbβ3 surface expression was reduced to <10% as measured by flow cytometry (PP4_Moderate). Although this variant was reported in heterozygosity in this individual (Patient GM in PMID: 12083483), PM3 was not applied at any level of strength because additional ITGA2B variants were also observed in the individual (c.2254C>G (p.Leu752Val) in homozygosity and c.2264G>C (p.Arg755Pro) in homozygosity). The highest gnomADv4.0 MAF is 0.000002858 (1/349874 alleles) in the European non-Finnish population (PM2_supporting). Furthermore, the computational predictor REVEL gives a score of 0.865, which is above the ClinGen Platelet Disorders VCEP threshold of >0.7 and predicts a damaging effect on function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD-VCEP: PP4_Moderate, PM2_Supporting, PP3. (VCEP specifications version 2.1; date of approval 4/16/2024) |
| Labcorp Genetics |
RCV002511547 | SCV003496160 | uncertain significance | Glanzmann thrombasthenia | 2022-08-12 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant is also known as G349D. This missense change has been observed in individual(s) with Glanzmann thrombasthenia (PMID: 12083483). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 380 of the ITGA2B protein (p.Gly380Asp). |