ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.1210+105A>G

gnomAD frequency: 0.00001  dbSNP: rs992856733
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV000851670 SCV002525906 likely pathogenic Glanzmann thrombasthenia 2022-04-13 reviewed by expert panel curation The NM_000419.5(ITGA2B):c.1210+105A>G intronic variant is absent from gnomAD v2.1.1 (PM2_Supporting). It is predicted, by SpliceAI (score 0.89), to cause gain of a donor splice site in intron 12. Electrophoresis gel results of PCR amplicons of platelet cDNA from patient TGP0060 confirmed that aberrant splicing occurred, and Sanger sequencing of the aberrant splice products found two mRNAs, one with a deletion of all of exon 13 coding sequence (p.Ile405_Asp465del) and the second with a 123 bp deletion (41 amino acids) in the exon 13 coding sequence (PM4; PMID: 31064749). This variant has been reported in two Glanzmann thrombasthenia patients, homozygote TGP0060 of PMID: 31064749 (PM3_supporting) and compound heterozygote GT10 in PMID:25373348 (in trans with Likely Pathogenic variant c.3091del). At least one patient (Patient GT10 in PMID:25373348) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia. Additionally, alphaIIbbeta3 surface expression was severely reduced, as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). In summary this variant meets criteria to be classified as Likely Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PP4_strong, PM2_supporting, PM3_supporting, PM4. (VCEP specifications version 2; date of approval 02/30/2022)
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851670 SCV000899454 uncertain significance Glanzmann thrombasthenia 2019-02-01 criteria provided, single submitter research

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