Gene Validity Curation

F5 - thrombophilia due to activated protein C resistance

Gene: F5 (HGNC:3542)
Classification - 09/30/2019
Disease: thrombophilia due to activated protein C resistance (MONDO_0008560)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The F5 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to activated protein C resistance, using the ClinGen Clinical Validity Framework as of 08/14/2018. This association was made using case-level and case-control data. Factor V Leiden is a missense variant that causes the amino acid change Arg534Gln, which results in the loss of the APC cleavage site and, therefore, APC resistance. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense variants with similar impact on APC resistance are also reported. F5 was first associated with this disease in humans as early as 1994 (Bertina et al., PMID: 8164741). Summary of Case Level Data (3.7 points): The association is seen in at least 16 probands in 6 publications (PMIDs: 28889200, 8164741, 7734374, 14617013, 27090446, 9454742). Variants in this gene segregated with disease in 6 additional family members. The Factor V Leiden variant has been reported in multiple publications from across the world. Summary of Case-Control Data (6.5 points): Association is seen in at least 3 case-control studies (PMID: 29179580, 11583312, 10666427, 26649017) at the single variant level. More case-control evidence is available in the literature. The mechanism for disease is gain of function, with the FVL variant and other missense variants observed causing resistance to inactivation by APC and therefore causing an increased risk of thrombosis. (PMID: 8164741). Summary of Experimental Data (4 points): This gene-disease relationship is supported by functional evidence and mouse models that recapitulate human disease (PMID: 16268462, 11110695, 9616155, 3286010). In summary, the F5- Thrombophilia due to activated protein C resistance 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 September 30, 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 8
4.2
4.2
Bertina RM et al. 1994 May 5 (PMID:8164741); Mumford AD et al. 2003 Nov (PMID:14617013); Pezeshkpoor B et al. 2016 July (PMID:27090446); Beufé S et al. 1995 Mar (PMID:7734374); Williamson D et al. 1998 Feb 15 (PMID:9454742); Abdi AA et al. 2017 Nov (PMID:28889200); Voorberg J et al. 1994 Jun 18 (PMID:7911872); Nogami K et al. 2014 Apr 10 (PMID:24523236);
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 1.81 1
Beufé S et al. 1995 Mar (PMID:7734374);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.81    
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 4
6.5
6.5
Saeed A et al. 2015 Sep-Oct (PMID:26649017); Gerhardt A et al. 2000 Feb 10 (PMID:10666427); Amara A et al. 2018 Mar (PMID:29179580); Emmerich J et al. 2001 Sep (PMID:11583312);
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 10.7
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
0.5
Furie B et al. 1988 May 20 (PMID:3286010);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
0
0.5
Nicolaes GA et al. 1995 Sep 8 (PMID:7673148);
Non-patient cells 0.5 0 - 1 1 0.5
Yang TL et al. 1998 Jun 15 (PMID:9616155);
Models Non-human model organism 2 0 - 4 4 2 3 3
Cooley BC et al. 2005 Sep (PMID:16268462); Cui J et al. 2000 Dec 15 (PMID:11110695);
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) 4

 


 

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 10.7 4 14.7 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
10/25/2019
EXPERT CURATION (DATE)
Definitive
09/30/2019
EVIDENCE SUMMARY
The F5 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to activated protein C resistance, using the ClinGen Clinical Validity Framework as of 08/14/2018. This association was made using case-level and case-control data. Factor V Leiden is a missense variant that causes the amino acid change Arg534Gln, which results in the loss of the APC cleavage site and, therefore, APC resistance. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense variants with similar impact on APC resistance are also reported. F5 was first associated with this disease in humans as early as 1994 (Bertina et al., PMID: 8164741). Summary of Case Level Data (3.7 points): The association is seen in at least 16 probands in 6 publications (PMIDs: 28889200, 8164741, 7734374, 14617013, 27090446, 9454742). Variants in this gene segregated with disease in 6 additional family members. The Factor V Leiden variant has been reported in multiple publications from across the world. Summary of Case-Control Data (6.5 points): Association is seen in at least 3 case-control studies (PMID: 29179580, 11583312, 10666427, 26649017) at the single variant level. More case-control evidence is available in the literature. The mechanism for disease is gain of function, with the FVL variant and other missense variants observed causing resistance to inactivation by APC and therefore causing an increased risk of thrombosis. (PMID: 8164741). Summary of Experimental Data (4 points): This gene-disease relationship is supported by functional evidence and mouse models that recapitulate human disease (PMID: 16268462, 11110695, 9616155, 3286010). In summary, the F5- Thrombophilia due to activated protein C resistance 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 September 30, 2019 (SOP Version 6).