ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
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: 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. "
Invitae RCV001378167 SCV001575678 likely pathogenic Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor IX defect 2020-09-15 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 279 of the F9 protein (p.Ala279Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with hemophilia B (PMID: 2066105, 27529981, 27865967, 23093250, 29656491). This variant is also known as Ala233Thr. ClinVar contains an entry for this variant (Variation ID: 216926). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.