ClinVar

Description

The F9 c.127C>T; p.Arg43Trp variant, also known as p.Arg-4Trp, is reported in the literature in numerous individuals affected with moderate to severe hemophilia B (Chavali 2009, Green 1992, Knobloch 1993, Li 2014, Factor IX database and references therein). Additional variants at the same codon (p.Arg43Gln, p.Arg43Leu) have been reported in individuals with hemophilia B and are considered pathogenic (Chavali 2009, Green 1992, Knobloch 1993, Li 2014, Factor IX database). The arginine at codon 43 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that the p.Arg43Trp variant is deleterious. In assays of clotting activity, the p.Arg43Trp, p.Arg43Gln, and p.Arg43Leu variants generally exhibit less than 5% of wildtype activity, consistent with moderate to severe hemophilia (Chavali 2009, Green 1992, Factor IX database). The p.Arg43Trp variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. References: Factor IX database: http://www.factorix.org Chavali S et al. Hemophilia B is a quasi-quantitative condition with certain mutations showing phenotypic plasticity. Genomics. 2009 Dec;94(6):433-7. Green PM et al. Haplotype analysis of identical factor IX mutants using PCR. Thromb Haemost. 1992 Jan 23;67(1):66-9. Knobloch O et al. Recurrent mutations in the factor IX gene: founder effect or repeat de novo events. Investigation of the German haemophilia B population and review of de novo mutations. Hum Genet. 1993 Aug;92(1):40-8. Li T et al. Mutation analysis of a cohort of US patients with hemophilia B. Am J Hematol. 2014 Apr;89(4):375-9.