ClinVar

Description

The NM_000212.3:c.674del (p.Gln225ArgfsTer2) variant in ITGB3 exon 5 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 5/15 and is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in at least one proband with Glanzmann thrombasthenia. The reported proband (GT30, PMID: 19691478) was homozygous for the variant (PM3_Supporting). At least one patient (Patient GT30 in PMID: 19691478) with this variant displayed mucocutaneous bleeding and impaired aggregation with all agonists except ristocetin, which is highly specific for Glanzmann thrombasthenia (PP4_Moderate). Additionally, alphaIIbbeta3 surface expression was reduced to <5%, as measured by flow cytometry. However, ITGA2B and ITGB3 were not reported to be sequenced across all exons and intron/exon boundaries. 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, PM2_Supporting, PM3_Supporting, PP4_Moderate. (VCEP specifications version 2; date of approval 05/17/2022)