The F5 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to activated protein C resistance, using the ClinGen Clinical Validity Framework as of 08/14/2018. This association was made using case-level and case-control data. Factor V Leiden is a missense variant that causes the amino acid change Arg534Gln, which results in the loss of the APC cleavage site and, therefore, APC resistance. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense variants with similar impact on APC resistance are also reported. F5 was first associated with this disease in humans as early as 1994 (Bertina et al., PMID: 8164741).
Summary of Case Level Data (3.7 points): The association is seen in at least 16 probands in 6 publications (PMIDs: 28889200, 8164741, 7734374, 14617013, 27090446, 9454742). Variants in this gene segregated with disease in 6 additional family members. The Factor V Leiden variant has been reported in multiple publications from across the world.
Summary of Case-Control Data (6.5 points): Association is seen in at least 3 case-control studies (PMID: 29179580, 11583312, 10666427, 26649017) at the single variant level. More case-control evidence is available in the literature.
The mechanism for disease is gain of function, with the FVL variant and other missense variants observed causing resistance to inactivation by APC and therefore causing an increased risk of thrombosis. (PMID: 8164741).
Summary of Experimental Data (4 points): This gene-disease relationship is supported by functional evidence and mouse models that recapitulate human disease (PMID: 16268462, 11110695, 9616155, 3286010).
In summary, the F5- Thrombophilia due to activated protein C resistance 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 September 30, 2019 (SOP Version 6).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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