ClinVar

Description

The F9 c.1120G>T; p.Val374Phe variant (rs137852271) is reported in the literature in multiple individuals affected with moderate to severe hemophilia B (Belvini 2005, Costa 2000, Giannelli 1994, Knobloch 1993, Winship 1990). This variant is reported in ClinVar (Variation ID: 10639), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 374 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, another variant at this codon (c.1120G>A, p.Val374Ile) has been reported in individuals with moderate hemophilia B and is considered pathogenic (Giannelli 1994, Poort 1990). Based on available information, the p.Val374Phe variant is considered to be pathogenic. References: Belvini D et al. Molecular genotyping of the Italian cohort of patients with hemophilia B. Haematologica. 2005 May;90(5):635-42. Costa JM et al. Fast and efficient mutation detection method using multiplex PCR and cycle sequencing--application to haemophilia B. Thromb Haemost. 2000 Feb;83(2):244-7. Giannelli F et al. Haemophilia B: database of point mutations and short additions and deletions, fifth edition, 1994. Nucleic Acids Res. 1994 Sep;22(17):3534-46. 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. Poort SR et al. Two mutations of the factor IX gene including a donor splice consensus deletion and a point mutation in a Dutch patient with severe hemophilia B. Thromb Haemost. 1990 Nov 30;64(3):379-84. Winship PR. Haemophilia B caused by mutation of a potential thrombin cleavage site in factor IX. Nucleic Acids Res. 1990 Mar 11;18(5):1310.