Submissions for variant NM_000212.3(ITGB3):c.2222G>A (p.Trp741Ter)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen	RCV004577683	SCV005061690	pathogenic	Glanzmann thrombasthenia	2024-05-02	reviewed by expert panel	curation	The c.2222G>A (p.Trp741Ter) variant in exon 14 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 14 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Surface expression of αIIb and β3 measured by Western blot in HEK293T cells transiently co-transfected with the c.2222G>A (p.Trp741Ter) variant β3 and wild type αIIb and β3 showed decreased expression at 0% WT levels, indicating that this variant impacts protein function (PMID: 37604334) (PS3_supporting). This variant has been detected in at least 1 proband with Glanzmann thrombasthenia (PMID: 37604334). This individual was compound heterozygous for this variant and a SINE-VNTR-Alu (SVA) retrotransposon insertion in ITGB3. This patient (Proband from PMID: 37604334) 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 reduced to 0.25% as measured by flow cytometry. ITGA2B and ITGB3 were sequenced across all exons and intron/exon boundaries. (PP4_strong). This variant is absent from gnomAD v4.0.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: PVS1, PS3_supporting, PP4_Strong and PM2_Supporting (VCEP specifications version 2; date of approval 05/02/2024).