Submissions for variant NM_000419.5(ITGA2B):c.1946+3G>T

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV003222569	SCV003915988	likely pathogenic	Glanzmann thrombasthenia	2023-03-21	reviewed by expert panel	curation	The NM_000419.5(ITGA2B):c.1946+3G>T variant is a splice region variant located in intron 19, which is absent from large population databases (gnomADv2.1.1; PM2_supporting). Two probands (GT65, GT34 of PMID:25728920) with this variant presented with significant mucocutaneous bleeding and platelet aggregometry demonstrated absence of platelet aggregation with 3 platelet agonists and normal aggregation with ristocetin. A reduced (<5%) surface expression of αIIbβ3 was demonstrated by flow cytometry (PP4_strong). Sanger sequencing ensured coverage of exons and splice sites of the ITGA2B and ITGB3 genes as well as untranslated regions. The c.1946+3G>T variant on ITGA2B is present in compound heterozygous state (GT65) with another splice donor variant c.574+1G>A , which has been previously classified as pathogenic by the PD-VCEP. (PM3_supporting). This variant meets criteria for PP4_strong, PM2_supporting, and PM3_supporting , and has been classified as likely pathogenic for Glanzmann thrombasthenia based on ACMG/AMP criteria specified by the Platelet Disorders VCEP.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388176	SCV004099588	likely pathogenic	Glanzmann thrombasthenia 1	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: ITGA2B c.1946+3G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 175102 control chromosomes (gnomAD). c.1946+3G>T has been reported in the literature in individuals affected with Glanzmann thrombasthenia 1 (Nurden_2015). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25728920, 27469266, 29385657). One submitter (ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen) has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.