ClinVar Miner

Submissions for variant NM_000133.3(F9):c.835G>A (p.Ala279Thr) (rs137852247)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000197147 SCV000255368 pathogenic Hereditary factor IX deficiency disease 2014-07-15 criteria provided, single submitter clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851896 SCV000899961 pathogenic Hereditary factor VIII deficiency disease 2019-02-01 criteria provided, single submitter research
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851897 SCV000899962 likely pathogenic Abnormality of coagulation 2019-02-01 criteria provided, single submitter research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000166 SCV001156654 pathogenic not specified 2018-11-09 criteria provided, single submitter clinical testing The F9 c.835G>A; p.Ala279Thr variant (rs137852247), also known as p.Ala233Thr, is reported in the literature in numerous individuals affected with hemophilia B and is primarily associated with mild disease (Chavali 2009, Chen 1991, Hamasaki-Katagiri 2012, Kihlberg 2017, Factor IX database and references therein). This is a recurrent missense variant observed in many affected individuals due both to a founder effect and to its location in a CpG dinucleotide, which are prone to G-to-A or C-to-T transitions (Chen 1991, Lassalle 2018). Clotting activity assays indicate the p.Ala279Thr variant exhibits approximately 10-15% of wildtype activity, consistent with mild hemophilia (Chavali 2009, Chen 1991, Kihlberg 2017, Factor IX database). This variant is reported in ClinVar (Variation ID: 216926) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 279 is highly conserved and occurs in the catalytic serine protease domain, computational analyses (SIFT, PolyPhen-2) predict that the p.Ala279Thr variant is deleterious, and another variant at this codon (p.Ala279Ser) is reported in an individual with hemophilia B (Rydz 2013), suggesting this amino acid is functionally important. Based on available information, the p.Ala279Thr 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. Chen SH et al. CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series. Hum Genet. 1991 Jun;87(2):177-82. Hamasaki-Katagiri N et al. Analysis of F9 point mutations and their correlation to severity of haemophilia B disease. Haemophilia. 2012 Nov;18(6):933-40. Kihlberg K et al. Discrepancies between the one-stage clotting assay and the chromogenic assay in haemophilia B. Haemophilia. 2017 Jul;23(4):620-627. Lassalle F et al. Recurrent F8 and F9 gene variants result from a founder effect in two large French haemophilia cohorts. Haemophilia. 2018 Apr 14. Rydz N et al. The Canadian National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013 Dec;88(12):1030-4. "

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