ClinVar Miner

Submissions for variant NM_000132.3(F8):c.6622C>G (p.Gln2208Glu) (rs1472169963)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000941 SCV001158040 pathogenic Hereditary factor VIII deficiency disease 2018-12-05 criteria provided, single submitter clinical testing The F8 c.6622C>G; p.Gln2208Glu variant, also known as Q2189E, is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (David 2006, Fernandez-Lopez 2005, Johnsen 2017, Markoff 2009). This variant is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamine at codon 2208 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.6623A>G, p.Gln2208Arg; c.6623A>C, p.Gln2208Pro) have been reported in individuals with mild to moderate hemophilia A and are considered pathogenic (Casana 2008, Cid 2007, Fernandez-Lopez 2005, Markoff 2009). Based on available information, the p.Gln2208Glu variant is considered to be pathogenic. References: Casana P et al. Severe and moderate hemophilia A: identification of 38 new genetic alterations. Haematologica. 2008 Jul;93(7):1091-4. Cid AR et al. Treatment in a haemophiliac A patient with paroxysmal atrial fibrillation and ischemic heart disease. Haemophilia. 2007 Nov;13(6):760-2. David D et al. The spectrum of mutations and molecular pathogenesis of hemophilia A in 181 Portuguese patients. Haematologica. 2006 Jun;91(6):840-3. Fernandez-Lopez O et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica. 2005 May;90(5):707-10. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41.

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