Gene Validity Curation

F10 - congenital factor X deficiency

Gene: F10 (HGNC:3528)
Classification - 11/27/2019
Disease: congenital factor X deficiency (MONDO_0009212)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between F10 and congenital factor X deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of November, 2019. This association was made using case-level and experimental data. More than a 100 variants in this gene are reported in humans, ranging from deletions, duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor X deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT and PT and reduced Factor X activity levels. Mutations in F10 were first associated with this disease in humans as early as 1989 by Reddy et al. (PMID: 2790181). Summary of Case Level Data (12 points): The association is seen in at least 14 probands in 7 publications (PMID: 30036279, 1985698, 10746568, 30507709, 2790181, 1939653, 22931370). 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 have been reported to be biallelic loss of function, although a number of individuals with heterozygous variants showing mild to moderate FX deficiency are reported in the literature (PMID: 10746568). Some of these occurrences are noted in the genetic evidence, but not scored. Summary of Experimental Data (4.5 points): FX activates prothrombin to thrombin in the blood coagulation pathway (PMID: 3286010). Mouse models that have the F10 gene knocked out show embryonic and perinatal lethality (PMID: 27626380, 10739370, 18036190); however, the mouse model with a missense variant, FX Friuli recapitulates FX deficiency in humans. The evidence from the mouse models parallel that seen in humans, where a complete loss of FX activity has not been reported in any patients. In summary, the F10-Congenital FX 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 Nov 27, 2019. (SOP Version 7)
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
10.5
12
Millar DS et al. 2000 Feb (PMID:10746568); Zhou JW et al. 2013 Jan (PMID:22931370); Reddy SV et al. 1989 Oct (PMID:2790181); Mitchell M et al. 2019 Jan (PMID:30507709); Borhany M et al. 2018 Nov (PMID:30036279);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 12
2.85
Millar DS et al. 2000 Feb (PMID:10746568); Watzke HH et al. 1991 Nov (PMID:1939653); James HL et al. 1991 Jan 15 (PMID:1985698); Mitchell M et al. 2019 Jan (PMID:30507709);
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 2 4
Dickinson ME et al. 2016 Sep 22 (PMID:27626380); Dewerchin M et al. 2000 Feb (PMID:10739370);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Tai SJ et al. 2008 Feb (PMID:18036190);
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
12/03/2019
EXPERT CURATION (DATE)
Definitive
11/27/2019
EVIDENCE SUMMARY
The relationship between F10 and congenital factor X deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of November, 2019. This association was made using case-level and experimental data. More than a 100 variants in this gene are reported in humans, ranging from deletions, duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor X deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT and PT and reduced Factor X activity levels. Mutations in F10 were first associated with this disease in humans as early as 1989 by Reddy et al. (PMID: 2790181). Summary of Case Level Data (12 points): The association is seen in at least 14 probands in 7 publications (PMID: 30036279, 1985698, 10746568, 30507709, 2790181, 1939653, 22931370). 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 have been reported to be biallelic loss of function, although a number of individuals with heterozygous variants showing mild to moderate FX deficiency are reported in the literature (PMID: 10746568). Some of these occurrences are noted in the genetic evidence, but not scored. Summary of Experimental Data (4.5 points): FX activates prothrombin to thrombin in the blood coagulation pathway (PMID: 3286010). Mouse models that have the F10 gene knocked out show embryonic and perinatal lethality (PMID: 27626380, 10739370, 18036190); however, the mouse model with a missense variant, FX Friuli recapitulates FX deficiency in humans. The evidence from the mouse models parallel that seen in humans, where a complete loss of FX activity has not been reported in any patients. In summary, the F10-Congenital FX 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 Nov 27, 2019. (SOP Version 7)