Gene Validity Curation

F9 - thrombophilia, X-linked, due to factor 9 defect

Gene: F9 (HGNC:3551)
Classification - 06/24/2020
Disease: thrombophilia, X-linked, due to factor 9 defect (MONDO_0010432)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: NO Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between F9 and thrombophilia due to factor 9 defect, an X-linked disorder, was evaluated using the ClinGen Clinical Validity Framework as of October, 2018. F9 encodes coagulation factor FIX that forms the tenase complex with FVII to activate FX in the coagulation cascade. F9 was first reported in relation to X-linked thrombophilia due to factor 9 defect in 2009 (Simioni et al, PMID: 19846852). Only one missense variant has been reported in relation to thrombophilia. While a few other polymorphisms, including F9 Malmo have been reported in association with risk of deep vein thrombosis, the biological mechanism for the association is not known. These variants have not been included in this curation. Evidence supporting this gene-disease relationship includes case-level data only. Summary of Case Level Data (1 points): Only 2 siblings from 1 publication have been reported with the hemizygous missense variant, Arg384Leu (PMID: 19846852). The mechanism is reported to be gain of function. No experimental evidence, other than functional studies on the Arg384Leu variant (PMID: 9575152) is available. In summary, the level of evidence to support the gene-disease relationship of F9 and X-linked thrombophilia due to factor 9 defect is limited. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on June 24, 2020 (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 1
1
1
Simioni P et al. 2009 Oct 22 (PMID:19846852);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
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) 1
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2
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
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) 0

 


 

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 1 0 1 NO
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)
Limited
06/24/2020
EXPERT CURATION (DATE)
Limited
06/24/2020
EVIDENCE SUMMARY
The relationship between F9 and thrombophilia due to factor 9 defect, an X-linked disorder, was evaluated using the ClinGen Clinical Validity Framework as of October, 2018. F9 encodes coagulation factor FIX that forms the tenase complex with FVII to activate FX in the coagulation cascade. F9 was first reported in relation to X-linked thrombophilia due to factor 9 defect in 2009 (Simioni et al, PMID: 19846852). Only one missense variant has been reported in relation to thrombophilia. While a few other polymorphisms, including F9 Malmo have been reported in association with risk of deep vein thrombosis, the biological mechanism for the association is not known. These variants have not been included in this curation. Evidence supporting this gene-disease relationship includes case-level data only. Summary of Case Level Data (1 points): Only 2 siblings from 1 publication have been reported with the hemizygous missense variant, Arg384Leu (PMID: 19846852). The mechanism is reported to be gain of function. No experimental evidence, other than functional studies on the Arg384Leu variant (PMID: 9575152) is available. In summary, the level of evidence to support the gene-disease relationship of F9 and X-linked thrombophilia due to factor 9 defect is limited. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hemostasis/Thrombosis GCEP on June 24, 2020 (SOP Version 6).