ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.2898_2902dup (p.Tyr968fs)

dbSNP: rs2143429307
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV001580216 SCV001809849 likely pathogenic Glanzmann thrombasthenia 2024-08-20 reviewed by expert panel curation The ITGA2B NM_000419.5:c.2898_2902dup variant has been experimentally determined to result in two mRNA products: a major product lacking exon 28 and a minor product containing exon 28 with a disrupted reading frame and native stop codon loss (PMID: 16463284), altering the entire transmembrane domain which is critically important. Exon 28 skipping is an in frame event predicted to lead to the production of a protein lacking amino acids 948-981. Loss of exon 28 has been demonstrated to result in the production of GPIIb/IIIa heterodimers that fail to complete post-translational processing and are retained intracellularly where they undergo degradation (PMID: 1932748), suggesting exon 28 is critical to protein function (PVS1). This variant has been observed in homozygosity (PM3_supporting) in one individual with a phenotype specific for Glanzmann's thrombasthenia (GT) (GT24, PMID: 16463284); history of bleeding and impaired aggregation to at least two agonists, but normal or only mildly reduced agglutination with ristocetin (PP4_Moderate). Furthermore, this variant is absent from population databases, including gnomADv4.1.0 (PM2_supporting). In summary, this variant meets criteria to be classified as likely pathogenic for GT. GT-specific criteria applied: PVS1_strong, PP4_moderate, PM2_supporting, and PM3_supporting.

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