ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.2348+5G>C

dbSNP: rs776442328
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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 RCV001580222 SCV001809856 pathogenic Glanzmann thrombasthenia 2021-04-20 reviewed by expert panel curation The ITGA2B intronic variant NM_000419.5:c.2348+5G>C is predicted by multiple in silico tools to lead to loss of the proximal canonical splice donor. In vitro minigene assays and sequence analysis (PMID: 25728920) support these predictions, suggesting the variant results in nearly complete in-frame skipping of exon 23, reducing the protein length by 27 amino acid residues (p.Ser756Gly783delinsArg). Additional functional studies in COS-7 cells indicate exon 23 skipping leads to significantly reduced surface protein expression (<10% compared to wild type) due to a block in integrin maturation (PMID: 25728920). This variant has been observed in homozygosity in an individual (GT8 in PMID: 25728920) with a phenotype specific for Glanzmann's thrombasthenia (GT). Furthermore, the variant is absent from control population databases. In summary, this variant meets criteria to be classified as pathogenic for GT. GT-specific criteria applied: PP4_strong, PM4, PS3_moderate, PP3, PM2_supporting, PM3_supporting.

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