ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.2613del (p.Leu872fs)

dbSNP: rs2048535976
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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 RCV001290452 SCV001478485 pathogenic Glanzmann thrombasthenia 2024-08-20 reviewed by expert panel curation The NM_000419.5(ITGA2B):c.2613del (p.Leu872CysfsTer38) frameshift variant generates a premature stop codon in exon 27 of 30 and is predicted to result in NMD (PVS1). The variant is absent from population databases including gnomADv4.1.0 (PM2_supporting). It has been reported in one Glanzmann thrombasthenia patient (PMID: 29675921) however a second ITGA2B variant was not identified. That patient is not considered in analysis of this variant as the authors provide no explanation for how the proposed genotype of the patient (heterozygous ITGA2B c.2613del/heterozygous ITGB3 Cys549Ser) could explain the GT phenotype and the possibility that biallelic variation in ITGB3 is responsible could not be ruled out. The possibility of a large deletion or duplication on the opposite allele has not been assessed. An additional GT proband (https://doi.org/10.1182/blood-2023-182694) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_moderate). Additionally, αIIbβ3 surface expression was absent or reduced, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. In summary, this variant meets criteria to be classified as Pathogenic for GT. GT-specific criteria applied: PVS1, PP4_Moderate and PM2_Supporting.

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