Submissions for variant NM_000419.5(ITGA2B):c.310+3_310+6del

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV002511545	SCV002820941	likely pathogenic	Glanzmann thrombasthenia	2022-04-07	reviewed by expert panel	curation	The NM_000419.5 (ITGA2B):c.310+3_310+6del intronic variant is predicted to disrupt the donor splice site of intron 2; the computational splicing predictor SpliceAI gives a score of 0.97 for donor loss (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient (Patient GT3 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, αIIbβ3 surface expression was <5%, as measured by flow cytometry while αIIb was absent on Western blot and β3 was decreased. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries (PP4_strong). GT3 of PMID: 25373348 is homozygous for this variant (PMm3_supporting). In summary, this variant meets the 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, PP3. (VCEP specifications version 2; date of approval 20/03/2022)