Submission Details

F7 was reported in relation to autosomal recessive Factor VII deficiency as early as 1996 (Arbini et al., PMID: 8652821). More than 100 pathogenic variants in this gene are reported in humans, ranging from deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Factor VII deficiency is characterized by a bleeding diathesis, with an increased prothrombin time, but normal activated partial thromboplastin time, reduced Factor VII activity and antigen levels. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 9 probands in 6 publications (PMIDs: 8652821, 11091194, 22628013, 10959697, 23141848, 11529858). More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is homozygous loss of function. Summary of Experimental Data (4.5 points): FVII is involved in the blood coagulation pathway and functions to activate FX in complex with Tissue Factor (PMID: 3286010). Mouse models recapitulate the human bleeding phenotype, but bleeding is more severe in mice (PMID: 9384381). AAV-mediated expression of FVII is shown to rescue bleeding in dog models (PMID: 26702064). In summary, the F7-Factor VII 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.