ITGB3

Inheritance Pattern: AR

Disease ID:MONDO:0010119

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100326

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0015372

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0030996

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030996

Submitter: ClinGen

*ITGB3* was first reported in relation to Autosomal Dominant Platelet-Type Bleeding Disorder 24 in 2008 (Ghevaert et al., PMID: 18065693). Several missense, in-frame deletions and splice-site variants have been reported so far in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Summary of Case Level Data (8 points): Variants in this gene have been reported in at least 26 probands in 14 publications (PMID: 29439184, 18065693, 19336737, 20081061, 24498605, 23253071, 19329429, 29380037, 29090484, 29296966, 31064749, 33276370, 37515626, 38151855) and 3 ClinVar entries (SCV004013088.1, SCV002540772.2, SCV002569362.1). Variants in this gene segregated with disease in 25 additional family members. The mechanism for disease is reported to be heterozygous gain-of-function, that results in constitutive, although partial, activation of the αIIbβ3 receptor complex. (PMID: 18065693, 19336737). Of note, this gene has also been implicated in autosomal recessive Glanzmann Thrombasthenia, and phenotypic overlap exists to an extent. Homozygous activating mutations involving Cysteine residues in β3 have also been reported, but with a normal platelet count and volume. These are associated with the typical GT or a GT-like phenotype (PMID: 22102273, 11588040). EXPERIMENTAL EVIDENCE: (3.5 points): This gene-disease association is supported by in vitro functional assays that show that the receptor complex is in a state of constitutive activation (PMID: 12816866). *ITGB3* encodes the integrin β3 glycoprotein and ITGA2B encodes the integrin αIIb glycoprotein. They interact to form the subunits of the αIIbβ3 complex, which is a platelet receptor for fibrinogen, among other ligands (PMID: 6460044). Thus the complex normally plays a significant role in platelet spreading and enabling clot formation. The gene-disease relationship is further supported by protein interaction, with *ITGA2B* (PMID: 6213621), and functional alteration in both patient (PMID: 18065693) and non-patient (PMID: 26452979) cells, indicating a defect in proplatelet formation. In summary, there is definitive evidence supporting the relationship between *ITGB3* and autosomal dominant platelet-type bleeding disorder 24. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was previously evaluated by the HT GCEP on 09/23/2020 and 04/03/2023. It was reevaluated on 05/29/2025 and five additional probands were identified (PMID:37515626, PMID:38151855, SCV004013088.1, SCV002540772.2, SCV002569362.1) increasing the classification from Moderate to Definitive. OMIM entities: Bleeding disorder, platelet-type, 24, autosomal dominant; Glanzmann thrombasthenia Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism(s) AND inheritance pattern AND phenotypic variability between the two conditions. Therefore, we have split curations for the disease entities, Glanzmann Thrombasthenia and platelet-type bleeding disorder 24. The *ITGB3*-Glanzmann Thrombasthenia gene-disease relationship has been evaluated separately.

Inheritance Pattern: AR

Disease ID:MONDO:0031009

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008552

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0031009

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030996

Submitter: Ambry Genetics