ClinVar

Description

The c.2941C>T (p.Gln981Ter) variant in exon 28 is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 28 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. Additionally, In two siblings, it has been shown that this mutation results in exon 28 being spliced out of the final protein product (PMID: 8111043, PVS1_Moderate). Surface expression of αIIb measured by Western blot in COS-1 cells transiently co-transfected with c.2941C>T (p.Gln981Ter) αIIb and wild type αIIb showed decreased expression at 0% of WT levels, indicating that this variant impacts protein function (PMID: 1932748)(PS3). At least two patients (Patient 1 and Patient 2 from PMID:8111043) 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% as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries (PP4_Moderate). This variant has also been reported to segregate with Glanzmann thrombasthenia in the proband (confirmed by bleeding phenotype and platelet aggregometry) plus the proband's affected sister. The c.2941C>T (p.Gln981Ter) variant is inherited from the patients' father and an unspecified ITGA2B variant is inherited from their mother (PP1_Supporting, PMID: 8111043). Finally, this variant is absent from gnomAD v2.1.1 (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, PP4_Moderate, PP1 and PM2_Supporting (VCEP specifications version 2.1).