Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

ITGA2B : Glanzmann's thrombasthenia

HGNC:6138 | MONDO_0010119
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hemostasis Thrombosis
SOP: Gene Clinical Validity Standard Operating Procedures (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 6
Burk CD et al. 1991 Jan (PMID:1702098); Jallu V et al. 2010 Mar (PMID:20020534);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
Wilcox DA et al. 1994 Feb 11 (PMID:7508443); Grimaldi CM et al. 1998 Mar 1 (PMID:9473221); Jallu V et al. 2010 Mar (PMID:20020534);
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
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 1 0.5
Grimaldi CM et al. 1998 Mar 1 (PMID:9473221);
Models Non-human model organism 2 0 - 4 4 1 2 2
Massberg S et al. 2005 Aug 23 (PMID:16103235);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 3.5 15.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The ITGA2B gene has been associated with the autosomal recessive condition, Glanzmann’s Thrombasthenia, using the ClinGen Clinical Validity Framework as of 01/14/2019. This association was made using case-level data only. At least 149 variants in this gene are reported in humans, including frameshifts, splicing variants, nonsense, and 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. ITGA2B was first associated with this disease in humans as early as 1991 (Burk et al., PMID: 1702098). Summary of Case Level Data: 12 POINTS The association is seen in at least 11 probands in 4 publications (PMIDs: 1702098, 9473221, 20020534, 7508443). 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 absent expression of the integrin αIIbβ3 receptor complex on the platelet surface (PMID: 2014236). Of note, this gene has also been implicated in a Glanzmann-like autosomal dominant bleeding disorder, platelet-type, 16 with the predominant observation of macrothrombocytopenia. The disease is suggested to result from activating mutations (PMIDs: 9834222, 21454453). This will be assessed separately. Summary of Experimental Data: 3.5 POINTS This gene-disease association is supported by biochemical function, protein interactions, functional alteration, and model systems. The pathological mechanism of the disease is impaired platelet aggregation due to diminished biochemical function (fibrinogen binding) of the αIIbβ3 receptor complex (PMID: 6460044). This gene encodes glycoprotein IIb, which interacts with the protein coded by ITGB3, glycoprotein IIIa, to form the αIIbβ3 receptor complex expressed on the surface of platelets and bind fibrinogen (PMID: 6213621). Functional alteration has been validated in non-patient cells, in which CHO cells expressing variant glycoprotein IIb have inhibited binding to fibrinogen (PMID: 9473221). The null mouse recapitulates the Glanzmann’s phenotype of impaired platelet aggregation (PMID: 16103235). Summary Statement DEFINITIVE In summary, ITGA2B is definitively associated with autosomal recessive Glanzmann’s Thrombasthenia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.