Gene Validity Curation

GP6 - platelet-type bleeding disorder 11

Gene: GP6 (HGNC:14388)
Classification - 10/23/2019
Disease: platelet-type bleeding disorder 11 (MONDO_0013623)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between GP6 and Platelet-type bleeding disorder 11, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of October 9, 2019. GP6 encodes the platelet membrane glycoprotein receptor for collagen. GPVI plays a critical role in collagen-induced platelet aggregation (PMID: 31351674, 31068042). Platelet-type bleeding disorder 11 is characterized by mild bleeding phenotypes and absent platelet aggregation in response to collagen (PMID: 31351674, 31068042). GP6 was first reported in relation to autosomal recessive Platelet-type bleeding disorder 11 in 2009 (Hermans et al, 2009; PMID: 19552682 and Dumont et al, 2009; PMID: 19549989). At least 5 missense and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (9.5 points): Variants in this gene have been reported in at least 6 probands in 3 publications (PMIDs: 19552682, 19549989, 23815599). The mechanism for disease is biallelic loss of function. Summary of Experimental Data (3.5 points): This gene-disease relationship is supported by animal models and expression studies. GP6-knock-out mice show absent platelet aggregation in response to collagen, similar to human patients (PMIDs: 12738669, 16139873) and platelets from GPVI-deficient mice are functionally abnormal (PMID: 12515812). The expression of GP6 is restricted to platelets and megakaryocytes (PMID: 10961879, 11278467). In summary, the GP6 - Platelet-type Bleeding Disorder 11 gene-disease relationship is definitive. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on October 23, 2019 (SOP Version 7).
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
9.5
9.5
Hermans C et al. 2009 Aug (PMID:19552682); Dumont B et al. 2009 Aug 27 (PMID:19549989); Matus V et al. 2013 Sep (PMID:23815599);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
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) 9.5
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
Massberg S et al. 2003 Jan 6 (PMID:12515812);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Jandrot-Perrus M et al. 2000 Sep 1 (PMID:10961879);
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 2.5 2.5
Kato K et al. 2003 Sep 1 (PMID:12738669);
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
(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 9.5 3.5 13 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
10/28/2019
EXPERT CURATION (DATE)
Definitive
10/23/2019
EVIDENCE SUMMARY
The relationship between GP6 and Platelet-type bleeding disorder 11, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of October 9, 2019. GP6 encodes the platelet membrane glycoprotein receptor for collagen. GPVI plays a critical role in collagen-induced platelet aggregation (PMID: 31351674, 31068042). Platelet-type bleeding disorder 11 is characterized by mild bleeding phenotypes and absent platelet aggregation in response to collagen (PMID: 31351674, 31068042). GP6 was first reported in relation to autosomal recessive Platelet-type bleeding disorder 11 in 2009 (Hermans et al, 2009; PMID: 19552682 and Dumont et al, 2009; PMID: 19549989). At least 5 missense and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Summary of Case Level Data (9.5 points): Variants in this gene have been reported in at least 6 probands in 3 publications (PMIDs: 19552682, 19549989, 23815599). The mechanism for disease is biallelic loss of function. Summary of Experimental Data (3.5 points): This gene-disease relationship is supported by animal models and expression studies. GP6-knock-out mice show absent platelet aggregation in response to collagen, similar to human patients (PMIDs: 12738669, 16139873) and platelets from GPVI-deficient mice are functionally abnormal (PMID: 12515812). The expression of GP6 is restricted to platelets and megakaryocytes (PMID: 10961879, 11278467). In summary, the GP6 - Platelet-type Bleeding Disorder 11 gene-disease relationship is definitive. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on October 23, 2019 (SOP Version 7).