ClinVar Miner

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

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Total submissions: 5
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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: 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

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