Submission Details

The F2 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to thrombin defect, using the ClinGen Clinical Validity Framework as of June, 2020. This association was made using case-level and case-control data. Prothrombin G20210A is a 3'UTR variant in the F2 gene that causes a gain of function and increased prothrombin synthesis. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense/regulatory region variants with similar gain of function impact are also reported. F2 was first associated with this disease in humans as early as 1996 (Poort et al., PMID: 8916933). Summary of Case Level Data (5.1 points): The association is seen in at least 7 probands in 7 publications (PMIDs: 8916933, 16988559, 27013614, 22716977, 23265743, 32194638, 11372696). Summary of Case-Control Data (9 points): Association between the prothrombin G20210A variant and thrombotic phenotype is seen in at least 4 case-control studies (PMID: 10027711, 29051591, 9669991, 8916933) at the single variant level. More case-control evidence is available in the literature. The mechanism for disease is gain of function, with the G20210A as well as other variants observed causing resistance to inactivation by antithrombin and therefore causing an increased risk of thrombosis. (PMID: 8916933, 11443298, 15059842). Summary of Experimental Data (1 point): This gene-disease relationship is supported by functional assay that shows upregulation of mRNA 3' end processing (PMID: 11443298, 15059842). In summary, the F2- Thrombophilia due to thrombin defect 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 June 24, 2020 (SOP Version 6).