Gene Validity Curation

ITGB3 - Glanzmann's thrombasthenia

Gene: ITGB3 (HGNC:6156)
Classification - 08/28/2019
Disease: Glanzmann's thrombasthenia (MONDO_0010119)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The ITGB3 gene has been associated with the Autosomal Recessive condition, Glanzmann’s 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).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 4
8.5
12
Newman PJ et al. 1991 Apr 15 (PMID:2014236); Jallu V et al. 2010 Mar (PMID:20020534); Ferrer M et al. 1998 Dec 15 (PMID:9845537);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
3.5
Jallu V et al. 2010 Mar (PMID:20020534); Laguerre M et al. 2013 Nov 13 (PMID:24236036); Peretz H et al. 2006 Apr (PMID:16463284);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
1
Nachman RL et al. 1982 Feb (PMID:6460044);
Protein Interaction 0.5 0 - 2 1 0.5
Jennings LK et al. 1982 Sep 10 (PMID:6213621);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 3 4
Hodivala-Dilke KM et al. 1999 Jan (PMID:9916135);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Fang J et al. 2005 Oct 15 (PMID:15972454);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 5 17 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
08/28/2019
EXPERT CURATION (DATE)
Definitive
08/28/2019
EVIDENCE SUMMARY
The ITGB3 gene has been associated with the Autosomal Recessive condition, Glanzmann’s 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).