ClinVar Miner

Submissions for variant NM_000133.3(F9):c.1025C>T (p.Thr342Met) (rs137852254)

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
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506908 SCV000603536 pathogenic not specified 2019-05-03 criteria provided, single submitter clinical testing The F9 c.1025C>T; p.Thr342Met variant (rs137852254), also known as Thr296Met, has been described in the literature in individuals with variable hemophilia B severity (see link to F9 database and references therein, Bicocchi 2006, Ketterline 1991, Radic 2013, Sharathkumar 2009). The variant is listed in the ClinVar database (Variation ID: 10607), and is absent from general population databases (Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at this position is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict this variant is deleterious. Additionally, other variants at this codon (c.1024A>G; p.Thr342Ala, c.1024A>C; p.Thr342Arg, c.1025C>A; p.Thr342Lys) have been described in individuals affected with hemophilia B and are considered pathogenic (see link to F9 database and references therein). Based on available information, the p.Thr342Met variant is considered pathogenic for hemophilia B with variable outcomes. REFERENCES Link to F9 database: http://www.factorix.org/ Bicocchi MP et al. Insight into molecular changes of the FIX protein in a series of Italian patients with haemophilia B. Haemophilia. 2006 12(3):263-70. Ketterling RP et al. T296----M, a common mutation causing mild hemophilia B in the Amish and others: founder effect, variability in factor IX activity assays, and rapid carrier detection. Hum Genet. 1991 87(3):333-7. Radic CP et al. Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B. Thromb Haemost. 2013 109(1):24-33. Sharathkumar A et al. Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C-->T mutation. Haemophilia. 2009 15(1):91-100.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851963 SCV000899402 likely pathogenic Hereditary factor VIII deficiency disease 2019-02-01 criteria provided, single submitter research
Invitae RCV000792734 SCV000932048 pathogenic Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor IX defect 2019-11-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 342 of the F9 protein (p.Thr342Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many individuals with hemophilia B and is considered to be a founder mutation in the Amish population (PMID: 2066105, 22639855, 1864609). This variant is also known as Thr296Met in the literature. ClinVar contains an entry for this variant (Variation ID: 10607). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000011353 SCV000031585 pathogenic Hereditary factor IX deficiency disease 1991-07-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000011353 SCV001161885 pathogenic Hereditary factor IX deficiency disease no assertion criteria provided research

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.