Gene Validity Curation

F7 - factor VII deficiency

Gene: F7 (HGNC:3544)
Classification - 07/24/2019
Disease: factor VII deficiency (MONDO_0002244)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: F7 was reported in relation to autosomal recessive Factor VII deficiency as early as 1996 (Arbini et al., PMID: 8652821). More than 100 pathogenic variants in this gene are reported in humans, ranging from deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Factor VII deficiency is characterized by a bleeding diathesis, with an increased prothrombin time, but normal activated partial thromboplastin time, reduced Factor VII activity and antigen levels. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 9 probands in 6 publications (PMIDs: 8652821, 11091194, 22628013, 10959697, 23141848, 11529858). More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is homozygous loss of function. Summary of Experimental Data (4.5 points): FVII is involved in the blood coagulation pathway and functions to activate FX in complex with Tissue Factor (PMID: 3286010). Mouse models recapitulate the human bleeding phenotype, but bleeding is more severe in mice (PMID: 9384381). AAV-mediated expression of FVII is shown to rescue bleeding in dog models (PMID: 26702064). In summary, the F7-Factor VII 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.
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 5
9
12
Arbini AA et al. 1996 Jun 15 (PMID:8652821); Suzuki K et al. 2013 Feb (PMID:23141848); Au WY et al. 2000 Oct (PMID:11091194); Takamiya O et al. 2001 Aug (PMID:11529858); Peyvandi F et al. 2000 Aug (PMID:10959697);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 4
3.5
Giansily-Blaizot M et al. 2012 Aug (PMID:22628013); Peyvandi F et al. 2000 Aug (PMID:10959697);
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
Rosen ED et al. 1997 Nov 20 (PMID:9384381);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Marcos-Contreras OA et al. 2016 Feb 4 (PMID:26702064);
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
07/15/2019
EXPERT CURATION (DATE)
Definitive
07/24/2019
EVIDENCE SUMMARY
F7 was reported in relation to autosomal recessive Factor VII deficiency as early as 1996 (Arbini et al., PMID: 8652821). More than 100 pathogenic variants in this gene are reported in humans, ranging from deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Factor VII deficiency is characterized by a bleeding diathesis, with an increased prothrombin time, but normal activated partial thromboplastin time, reduced Factor VII activity and antigen levels. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 9 probands in 6 publications (PMIDs: 8652821, 11091194, 22628013, 10959697, 23141848, 11529858). More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is homozygous loss of function. Summary of Experimental Data (4.5 points): FVII is involved in the blood coagulation pathway and functions to activate FX in complex with Tissue Factor (PMID: 3286010). Mouse models recapitulate the human bleeding phenotype, but bleeding is more severe in mice (PMID: 9384381). AAV-mediated expression of FVII is shown to rescue bleeding in dog models (PMID: 26702064). In summary, the F7-Factor VII 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.