Gene Validity Curation

F12 - hereditary angioedema type 3

Gene: F12 (HGNC:3530)
Classification - 01/23/2020
Disease: hereditary angioedema type 3 (MONDO_0012526)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: The relationship between F12 and Hereditary Angioedema type III (HAE-III) inherited in the autosomal dominant pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. HAE-III is characterized by recurrent skin swelling and abdominal pain attacks and differs from types I and II in that the concentration and function of C1-esterase inhibitor is normal. Specific heterozygous missense variants in the proline-rich domain of F12 cause HAE-III. Mutations in F12 were first associated with this disease in humans in 2006 by Cichon et al. (PMID: 17186468) and Dewald et al (PMID: 16638441 ). Summary of Case Level Data (3.5 points): The association is seen in at least 7 probands in 4 publications (PMID: 26193639, 16638441, 17381464, 21849258). The recurrent founder variant, Thr328Lys, is reported in several individuals with HAE-III. This variant segregated with disease in at least 17 additional family members. It appears that only variation at the Thr328 residue may result in the HAE-III phenotype. The mechanism for disease is expected to be heterozygous gain of function. Summary of Experimental Data (4.5 points): F12 is involved in the kallikrein-kinin cascade that results in the generation of braydkinin. Due to gain of function mutations in F12, excessive bradykinin is generated which results in increased vascular permeability (PMID: 30463937). An HAE-III transgenic mouse model with human-derived Thr328Lys variant recapitulates the human phenotype (PMID: 26193639). In summary, the F12-Hereditary Angioedema type III gene-disease relationship is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. 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 1 0 0
Gelincik A et al. 2015 Feb (PMID:25524745);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 9
2
2
Björkqvist J et al. 2015 Aug 3 (PMID:26193639); Dewald G et al. 2006 May 19 (PMID:16638441); Bouillet L et al. 2007 May (PMID:17381464); Bork K et al. 2011 Oct (PMID:21849258); Kiss N et al. 2013 Oct (PMID:23994767); Gelincik A et al. 2015 Feb (PMID:25524745);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 6.03 4
Björkqvist J et al. 2015 Aug 3 (PMID:26193639); Dewald G et al. 2006 May 19 (PMID:16638441);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 6.03    
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) 3.5
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
Liu J et al. 2019 Feb (PMID:30463937);
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 4 4
Björkqvist J et al. 2015 Aug 3 (PMID:26193639);
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 3.5 4.5 8 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)
Moderate
01/23/2020
EXPERT CURATION (DATE)
Moderate
01/23/2020
EVIDENCE SUMMARY
The relationship between F12 and Hereditary Angioedema type III (HAE-III) inherited in the autosomal dominant pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. HAE-III is characterized by recurrent skin swelling and abdominal pain attacks and differs from types I and II in that the concentration and function of C1-esterase inhibitor is normal. Specific heterozygous missense variants in the proline-rich domain of F12 cause HAE-III. Mutations in F12 were first associated with this disease in humans in 2006 by Cichon et al. (PMID: 17186468) and Dewald et al (PMID: 16638441 ). Summary of Case Level Data (3.5 points): The association is seen in at least 7 probands in 4 publications (PMID: 26193639, 16638441, 17381464, 21849258). The recurrent founder variant, Thr328Lys, is reported in several individuals with HAE-III. This variant segregated with disease in at least 17 additional family members. It appears that only variation at the Thr328 residue may result in the HAE-III phenotype. The mechanism for disease is expected to be heterozygous gain of function. Summary of Experimental Data (4.5 points): F12 is involved in the kallikrein-kinin cascade that results in the generation of braydkinin. Due to gain of function mutations in F12, excessive bradykinin is generated which results in increased vascular permeability (PMID: 30463937). An HAE-III transgenic mouse model with human-derived Thr328Lys variant recapitulates the human phenotype (PMID: 26193639). In summary, the F12-Hereditary Angioedema type III gene-disease relationship is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. 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.