Gene Validity Curation

F2 - thrombophilia due to thrombin defect

Gene: F2 (HGNC:3535)
Classification - 06/24/2020
Disease: thrombophilia due to thrombin defect (MONDO_0008559)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The F2 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to thrombin defect, using the ClinGen Clinical Validity Framework as of June, 2020. This association was made using case-level and case-control data. Prothrombin G20210A is a 3'UTR variant in the F2 gene that causes a gain of function and increased prothrombin synthesis. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense/regulatory region variants with similar gain of function impact are also reported. F2 was first associated with this disease in humans as early as 1996 (Poort et al., PMID: 8916933). Summary of Case Level Data (5.1 points): The association is seen in at least 7 probands in 7 publications (PMIDs: 8916933, 16988559, 27013614, 22716977, 23265743, 32194638, 11372696). Summary of Case-Control Data (9 points): Association between the prothrombin G20210A variant and thrombotic phenotype is seen in at least 4 case-control studies (PMID: 10027711, 29051591, 9669991, 8916933) at the single variant level. More case-control evidence is available in the literature. The mechanism for disease is gain of function, with the G20210A as well as other variants observed causing resistance to inactivation by antithrombin and therefore causing an increased risk of thrombosis. (PMID: 8916933, 11443298, 15059842). Summary of Experimental Data (1 point): This gene-disease relationship is supported by functional assay that shows upregulation of mRNA 3' end processing (PMID: 11443298, 15059842). In summary, the F2- Thrombophilia due to thrombin defect 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 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 7
5.1
5.1
Poort SR et al. 1996 Nov 15 (PMID:8916933); Miyawaki Y et al. 2012 Jun 21 (PMID:22716977); Wylenzek M et al. 2001 May (PMID:11372696); Dunn ST et al. 2006 Oct (PMID:16988559); Tang Y et al. 2020 Mar 3 (PMID:32194638); Sivasundar S et al. 2013 Mar (PMID:23265743); Bulato C et al. 2016 May (PMID:27013614);
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 0 0  
Candidate gene sequencing 1.2 1
Miyawaki Y et al. 2012 Jun 21 (PMID:22716977);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.2    
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 5
9
9
Poort SR et al. 1996 Nov 15 (PMID:8916933); Franco RF et al. 1999 Jan (PMID:10027711); Margaglione M et al. 1998 Jul 15 (PMID:9669991); Li C et al. 2017 Oct 19 (PMID:29051591); Martinelli I et al. 2006 Dec (PMID:16981886);
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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 1 1
Gehring NH et al. 2001 Aug (PMID:11443298);
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) 1

 


 

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 1 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
06/24/2020
EXPERT CURATION (DATE)
Definitive
06/24/2020
EVIDENCE SUMMARY
The F2 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to thrombin defect, using the ClinGen Clinical Validity Framework as of June, 2020. This association was made using case-level and case-control data. Prothrombin G20210A is a 3'UTR variant in the F2 gene that causes a gain of function and increased prothrombin synthesis. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense/regulatory region variants with similar gain of function impact are also reported. F2 was first associated with this disease in humans as early as 1996 (Poort et al., PMID: 8916933). Summary of Case Level Data (5.1 points): The association is seen in at least 7 probands in 7 publications (PMIDs: 8916933, 16988559, 27013614, 22716977, 23265743, 32194638, 11372696). Summary of Case-Control Data (9 points): Association between the prothrombin G20210A variant and thrombotic phenotype is seen in at least 4 case-control studies (PMID: 10027711, 29051591, 9669991, 8916933) at the single variant level. More case-control evidence is available in the literature. The mechanism for disease is gain of function, with the G20210A as well as other variants observed causing resistance to inactivation by antithrombin and therefore causing an increased risk of thrombosis. (PMID: 8916933, 11443298, 15059842). Summary of Experimental Data (1 point): This gene-disease relationship is supported by functional assay that shows upregulation of mRNA 3' end processing (PMID: 11443298, 15059842). In summary, the F2- Thrombophilia due to thrombin defect 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 GCEP on June 24, 2020 (SOP Version 6).