Gene Validity Curation

F5 - congenital factor V deficiency

Gene: F5 (HGNC:3542)
Classification - 03/25/2020
Disease: congenital factor V deficiency (MONDO_0009210)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The F5 gene has been associated with the Autosomal Recessive condition, Congenital Factor 5 Deficiency, using the ClinGen Clinical Validity Framework as of 08/29/2018. This association was made using case-level data only. Factor V deficiency, also called Parahemophilia, is rare and characterized by mild to severe bleeding diathesis. The disease was first described in 1947 by Owren et al. (PMID: 20293060). Factor V is essential for the activation of prothrombin and is a key component of the common pathway in the coagulation cascade. It has both procoagulant and anticoagulant properties and, thus, causes bleeding as well as thrombotic disorders. F5 mutations were first associated with congenital factor 5 deficiency in humans as early as 1998 (Guasch et al., PMID: 9576178). Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMIDs: 19486170, 9576178, 21777354, 18192108). Most of the reported variants are null or predicted null, including nonsense, frameshift and small deletions and insertions; however, a number of missense variants with functional evidence supporting their damaging effect are also reported. More genetic evidence is available in the literature, but the maximum allowable points for genetic evidence has been reached. The mechanism for disease is loss of function, with the majority of variants observed being null variants (frameshift/nonsense) and predicted or shown to result in reduced mRNA product due to nonsense-mediated decay (PMID: 9576178, 19486170). Summary of Experimental Data (4 points): This gene-disease relationship is supported by mouse models that recapitulate human disease and rescue of the disease phenotype (PMID: 8900278, 12855561, 10669158). The model system phenotype shows embryonic lethality for complete loss of FV activity, which indicates that non-lethal phenotype in humans may result due to residual activity of FV. In summary, the F5 – Congenital Factor V Deficiency 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 March 25, 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
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 6
12
12
Guasch JF et al. 1998 Apr (PMID:9576178); Delev D et al. 2009 Sep (PMID:19486170); Shinozawa K et al. 2007 Dec (PMID:18192108); Paraboschi EM et al. 2012 Mar (PMID:21777354);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 1
1
Shinozawa K et al. 2007 Dec (PMID:18192108);
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
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
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 4
Cui J et al. 1996 Nov 7 (PMID:8900278);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Yang TL et al. 2000 Jan (PMID:10669158);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

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 12 4.5 16.5 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
03/26/2020
EXPERT CURATION (DATE)
Definitive
03/25/2020
EVIDENCE SUMMARY
The F5 gene has been associated with the Autosomal Recessive condition, Congenital Factor 5 Deficiency, using the ClinGen Clinical Validity Framework as of 08/29/2018. This association was made using case-level data only. Factor V deficiency, also called Parahemophilia, is rare and characterized by mild to severe bleeding diathesis. The disease was first described in 1947 by Owren et al. (PMID: 20293060). Factor V is essential for the activation of prothrombin and is a key component of the common pathway in the coagulation cascade. It has both procoagulant and anticoagulant properties and, thus, causes bleeding as well as thrombotic disorders. F5 mutations were first associated with congenital factor 5 deficiency in humans as early as 1998 (Guasch et al., PMID: 9576178). Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMIDs: 19486170, 9576178, 21777354, 18192108). Most of the reported variants are null or predicted null, including nonsense, frameshift and small deletions and insertions; however, a number of missense variants with functional evidence supporting their damaging effect are also reported. More genetic evidence is available in the literature, but the maximum allowable points for genetic evidence has been reached. The mechanism for disease is loss of function, with the majority of variants observed being null variants (frameshift/nonsense) and predicted or shown to result in reduced mRNA product due to nonsense-mediated decay (PMID: 9576178, 19486170). Summary of Experimental Data (4 points): This gene-disease relationship is supported by mouse models that recapitulate human disease and rescue of the disease phenotype (PMID: 8900278, 12855561, 10669158). The model system phenotype shows embryonic lethality for complete loss of FV activity, which indicates that non-lethal phenotype in humans may result due to residual activity of FV. In summary, the F5 – Congenital Factor V Deficiency 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 March 25, 2020. (SOP Version 6)