Abstract
Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus-specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross-species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity.
Highlights
We report the development of the factor VII (FVII) gene (F7) Variant Database (f7‐db.eahad.org)
Severe patients are either homozygous or compound heterozygous for nonsense, canonical splice site, frameshift, missense variants resulting in the substitution of critical residues for the FVII function (viz., arginine residue at the proteolytic activation site (Arg212), the catalytic triad (Asp302), or residues involved in the disulfide bond (Cys195), between the light and heavy chains of the activated form of FVII), variants at transcription factor binding sites within the F7 promoter or variants predicted to dramatically alter the protein folding namely, p.(Gln160Arg) or p.(Thr419Met)
Variant classification is central to the utility of molecular genetic diagnostics in clinical practice; predicting whether gene
Summary
Whereas in the more common inherited bleeding disorders hemophilia A and B there is a good correlation between residual clotting activity and the severity of any associated bleeding; in FVII deficiency this relationship is less clear This might be explained by the lack of sensitivity in assays in differentiating between a total absence of FVII:C activity from extremely low levels. Neonatal central nervous system bleeds that are often fatal are characteristic of severely affected cases and arise in individuals with variants that result in extremely low or undetectable FVII levels This mirrors the phenotype observed in mice made null for F7 by homologous recombination who die either from fatal intra‐abdominal hemorrhage in the peripartum period or intracranial hemorrhage before the age of 24 days (Rosen et al, 1997). We report the development of the FVII gene (F7) Variant Database (f7‐db.eahad.org)
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