Gene Validity Curation

F11 - congenital factor XI deficiency

Gene: F11 (HGNC:3529)
Classification - 10/23/2019
Disease: congenital factor XI deficiency (MONDO_0012897)
Mode of Inheritance: Semidominant inheritance (HP:0032113)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between F11 and congenital factor XI deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of November, 2018. This association was made using case-level and experimental data. More than a 100 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XI deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT but normal PT and reduced factor XI activity and antigen levels. Mutations in F11 were first associated with this disease in humans as early as 1989 by Asakai et al. (PMID: 2813350). Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 5 publications (PMID: 15026311, 15953011, 15180874, 21649796, 2813350, 22159456). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease has been reported to be biallelic loss of function as well as a dominant negative effect (PMID: 15026311, 2813350). Summary of Experimental Data (4.5 points): FXI activates FIX in the blood coagulation pathway (PMID: 3286010). Mouse and cattle models are reported that recapitulate FXI deficiency (PMID: 15566468, 9518045). In Holstein cows, FXI deficiency is naturally occurring and leads to bleeding symptoms. The deficiency is also reported in dogs (PMID: 5166932). In summary, the F11-Congenital FXI 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 October 23, 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 3 4 4
Hill M et al. 2005 Jun (PMID:15953011);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 3
1.5
1.5
Hill M et al. 2005 Jun (PMID:15953011); Kravtsov DV et al. 2004 Jul 1 (PMID:15026311);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 6
8
9.25
Hill M et al. 2005 Jun (PMID:15953011); Dai L et al. 2004 Jun (PMID:15180874); Asakai R et al. 1989 Oct (PMID:2813350); Bicocchi MP et al. 2011 Sep (PMID:21649796);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 3
1.25
Asakai R et al. 1989 Oct (PMID:2813350); Bicocchi MP et al. 2011 Sep (PMID:21649796); Guéguen P et al. 2012 Jan (PMID:22159456);
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 2 4 4
Gailani D et al. 1997 Mar (PMID:9518045); Marron BM et al. 2004 Dec (PMID:15566468);
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) 4.5

 


 

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
10/25/2019
EXPERT CURATION (DATE)
Definitive
10/23/2019
EVIDENCE SUMMARY
The relationship between F11 and congenital factor XI deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of November, 2018. This association was made using case-level and experimental data. More than a 100 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XI deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT but normal PT and reduced factor XI activity and antigen levels. Mutations in F11 were first associated with this disease in humans as early as 1989 by Asakai et al. (PMID: 2813350). Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 5 publications (PMID: 15026311, 15953011, 15180874, 21649796, 2813350, 22159456). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease has been reported to be biallelic loss of function as well as a dominant negative effect (PMID: 15026311, 2813350). Summary of Experimental Data (4.5 points): FXI activates FIX in the blood coagulation pathway (PMID: 3286010). Mouse and cattle models are reported that recapitulate FXI deficiency (PMID: 15566468, 9518045). In Holstein cows, FXI deficiency is naturally occurring and leads to bleeding symptoms. The deficiency is also reported in dogs (PMID: 5166932). In summary, the F11-Congenital FXI 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 October 23, 2019 (SOP Version 6).