ITGB3 was first reported in relation to Autosomal Dominant Platelet-Type Bleeding Disorder 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 16. 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, 16, 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 16. The ITGB3-Glanzmann Thrombasthenia gene-disease relationship has been evaluated separately.
ITGB3 was first reported in relation to Autosomal Dominant Platelet-Type Bleeding Disorder 16 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 16. 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, 16, 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 16. The ITGB3-Glanzmann Thrombasthenia gene-disease relationship has been evaluated separately.
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