The F5 gene has been associated with the Autosomal Recessive condition, Congenital Factor 5 Deficiency, using the ClinGen Clinical Validity Framework as of 08/29/2018. This association was made using case-level data only. Factor V deficiency, also called Parahemophilia, is rare and characterized by mild to severe bleeding diathesis. The disease was first described in 1947 by Owren et al. (PMID: 20293060). Factor V is essential for the activation of prothrombin and is a key component of the common pathway in the coagulation cascade. It has both procoagulant and anticoagulant properties and, thus, causes bleeding as well as thrombotic disorders. F5 mutations were first associated with congenital factor 5 deficiency in humans as early as 1998 (Guasch et al., PMID: 9576178).
Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMIDs: 19486170, 9576178, 21777354, 18192108). Most of the reported variants are null or predicted null, including nonsense, frameshift and small deletions and insertions; however, a number of missense variants with functional evidence supporting their damaging effect are also reported. More genetic evidence is available in the literature, but the maximum allowable points for genetic evidence has been reached.
The mechanism for disease is loss of function, with the majority of variants observed being null variants (frameshift/nonsense) and predicted or shown to result in reduced mRNA product due to nonsense-mediated decay (PMID: 9576178, 19486170).
Summary of Experimental Data (4 points): This gene-disease relationship is supported by mouse models that recapitulate human disease and rescue of the disease phenotype (PMID: 8900278, 12855561, 10669158). The model system phenotype shows embryonic lethality for complete loss of FV activity, which indicates that non-lethal phenotype in humans may result due to residual activity of FV.
In summary, the F5 – Congenital Factor V 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 March 25, 2020. (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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