Submission Details

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 May, 2022. 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 (6.3 points): The association is seen in at least 31 probands in 6 publications (PMID: 26193639, 16638441, 17381464, 21849258, 25952149, 36203598). The recurrent founder variant, Thr328Lys (also known as Thr309Lys), is reported in the majority of individuals with HAE-III. This variant segregated with disease in at least 42 additional family members. It appears that only variation at the Thr328 residue may result in the HAE-III phenotype, with other reported variants of Thr328Arg and a deletion that includes Thr328.

The mechanism for disease is expected to be heterozygous gain of function.

Summary of Experimental Data (6 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). Functional data in plasma samples from HAE-FXIIThr309Lys patients and in transfected cell lines provide further support for non-canonical cleavage and activation of FXIIThr309Lys by thrombin as the cause of HAE (López-Gálvez R, et al., 2021, PMID: 33725261). An HAE-III transgenic mouse model with human-derived Thr328Lys variant recapitulates the human phenotype (PMID: 26193639).

In summary, there is definitive evidence supporting the relationship between F12 and autosomal dominant Hereditary Angioedema type III. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

This gene-disease pair was originally evaluated by the HT GCEP on 01/23/2020. It was reevaluated on 05/25/2022 and 06/03/2024. As a result of the most recent reevaluation, with the addition of 24 probands (PMIDs: 25952149, 36203598) the classificaiton increased from Moderate to Definitive.

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.