Gene Validity Curation

F12 - congenital factor XII deficiency

Gene: F12 (HGNC:3530)
Classification - 01/22/2020
Disease: congenital factor XII deficiency (MONDO_0009315)
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 F12 and congenital factor XII deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. Pathogenic variants in this gene reported in humans range from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XII deficiency does not manifest as overt clinical symptoms and is diagnosed as an incidental finding when patients are tested for other reasons. Studies indicate that FXII deficiency neither predisposes to venous thromboembolism nor protects against it (PMID: 25696836, 15306750). Nevertheless, mutations in F12 result in reduced activity with or without reduced antigen levels of FXII. Mutations in F12 were first associated with this disease in humans as early as 1987 by Bernardi et al. (PMID: 2882793); however, the molecular defect was reported by Miyata et al in 1989 (PMID: 2510163). Summary of Case Level Data (12 points): The association is seen in at least 11 probands in 8 publications (PMID: 29383625, 20022356, 18024408, 20386432, 26709783, 21264442, 28007010, 15205584). 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 is expected to be biallelic loss of function, with heterozygous individuals usually having intermediate levels of factor activity. Summary of Experimental Data (4 points): FXII is the first component of the intrinsic pathway of the coagulation cascade and activates FXI (PMID: 30700128). The significance of FXII in the coagulation pathway is not clear, however. Mouse models are reported that recapitulate FXII deficiency, without any clinical manifestations, suggesting that FXII deficiency does not affect hemostasis in vivo (PMID: 15351846). This is similar to what is observed in humans. In cats, FXII deficiency is a naturally occurring defect and leads to complete lack of FXII activity and antigen (PMID: 31022435). In summary, the F12-Congenital FXII 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 January 22, 2020 (SOP Version 7). Lumping & Splitting information: OMIM assertions - (1) Angioedema, hereditary, type III (MIM: 610618); (2) Factor XII deficiency (MIM: 234000). Orphanet assertions - (1) F12-related hereditary angioedema with normal C1Inh; (2) Congenital factor XII deficiency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the phenotype, inheritance pattern and molecular mechanism underlying the two disease entities to be different and hence the association of F12 with each entity was evaluated separately.
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 3
6
12
Mordillo C et al. 2007 Nov (PMID:18024408); Kwon MJ et al. 2010 Jun (PMID:20386432);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 8
6.5
Iijima K et al. 2011 Mar (PMID:21264442); Cheng X et al. 2017 Jun (PMID:28007010); Zou A et al. 2018 Apr (PMID:29383625); Jin P et al. 2016 Jan 1 (PMID:26709783); Suzuki K et al. 2010 May (PMID:20022356); Ishii K et al. 2004 Jul (PMID:15205584);
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
Grover SP et al. 2019 Mar (PMID:30700128);
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
Maruyama H et al. 2019 Jul 20 (PMID:31022435); Pauer HU et al. 2004 Sep (PMID:15351846);
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
01/23/2020
EXPERT CURATION (DATE)
Definitive
01/22/2020
EVIDENCE SUMMARY
The relationship between F12 and congenital factor XII deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. Pathogenic variants in this gene reported in humans range from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XII deficiency does not manifest as overt clinical symptoms and is diagnosed as an incidental finding when patients are tested for other reasons. Studies indicate that FXII deficiency neither predisposes to venous thromboembolism nor protects against it (PMID: 25696836, 15306750). Nevertheless, mutations in F12 result in reduced activity with or without reduced antigen levels of FXII. Mutations in F12 were first associated with this disease in humans as early as 1987 by Bernardi et al. (PMID: 2882793); however, the molecular defect was reported by Miyata et al in 1989 (PMID: 2510163). Summary of Case Level Data (12 points): The association is seen in at least 11 probands in 8 publications (PMID: 29383625, 20022356, 18024408, 20386432, 26709783, 21264442, 28007010, 15205584). 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 is expected to be biallelic loss of function, with heterozygous individuals usually having intermediate levels of factor activity. Summary of Experimental Data (4 points): FXII is the first component of the intrinsic pathway of the coagulation cascade and activates FXI (PMID: 30700128). The significance of FXII in the coagulation pathway is not clear, however. Mouse models are reported that recapitulate FXII deficiency, without any clinical manifestations, suggesting that FXII deficiency does not affect hemostasis in vivo (PMID: 15351846). This is similar to what is observed in humans. In cats, FXII deficiency is a naturally occurring defect and leads to complete lack of FXII activity and antigen (PMID: 31022435). In summary, the F12-Congenital FXII 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 January 22, 2020 (SOP Version 7). Lumping & Splitting information: OMIM assertions - (1) Angioedema, hereditary, type III (MIM: 610618); (2) Factor XII deficiency (MIM: 234000). Orphanet assertions - (1) F12-related hereditary angioedema with normal C1Inh; (2) Congenital factor XII deficiency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the phenotype, inheritance pattern and molecular mechanism underlying the two disease entities to be different and hence the association of F12 with each entity was evaluated separately.