Submission Details

The ITGB3 gene has been associated with the Autosomal Recessive condition Glanzmann Thrombasthenia, using the ClinGen Clinical Validity Framework as of 09/21/2018. This association was made using case-level data only. More than a 100 variants in this gene are reported in humans, ranging from deletions, nonsense, frameshift and splicing variants to a number of functionally characterized missense variants. Glanzmann’s Thrombasthenia is characterized by a bleeding diathesis diagnosed by an increased bleeding time, reduced platelet aggregation and lack of clot retraction. Variants in this gene were reported in an Iraqi-Jewish cohort (a possible founder variant) as early as 1991 (Newman et al., PMID: 2014236).

Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 5 publications (PMIDs: 9845537, 20020534, 2014236, 16463284, 24236036). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism for disease is biallelic loss of function, with the majority of variants observed resulting in reduced or absence of expression of the integrin αIIbβ3 receptor complex on the platelet surface (PMID: 2014236). An autosomal dominant Glanzmann-like disorder, Platelet-type Bleeding Disorder 16, is also reported in the literature with the predominant observation of macrothrombocytopenia. Gain of function variants causing constitutional activation of the receptor resulting in slightly increased binding of fibrinogen cause this condition (PMIDs: 24498605, 22102273, 20081061, 19336737). The relationship between ITGB3 and Platelet-type Bleeding Disorder 16 is evaluated separately.

Summary of Experimental Data (5 points): The pathological mechanism of the disease is the impaired binding of fibrinogen of the αIIbβ3 receptor complex, and experimental evidence elucidating ITGB3 protein function is well-characterized. This gene encodes the β3 glycoprotein, which interacts with the protein encoded by ITGA2B, αIIb, to form the αIIbβ3 receptor complex expressed on the surface of platelets and bind fibrinogen. (PMID: 6460044, 6213621). The β3-null mouse recapitulates the Glanzmann’s phenotype observed in humans and has been studied widely in the literature. (PMID: 9916135). The GT phenotype is also shown to be corrected in vivo using the β3-null mouse model, when transplanted with bone marrow transduced with human β3 cDNA.

In summary, the ITGB3-Glanzmann’s Thrombasthenia gene-disease relationship is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on August 28, 2019 (SOP Version 6).