Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000011064 | SCV001471614 | likely pathogenic | Hereditary factor VIII deficiency disease | 2020-08-24 | criteria provided, single submitter | clinical testing | The F8 c.592T>G; p.Cys198Gly variant (rs137852475), also known as Cys179Gly, is reported in the literature in several individuals affected with severe hemophilia A (Bogdanova 2005, Markoff 2009, Margaglione 2008, Mazurier 2002, Rydz 2013). This variant is reported in ClinVar (Variation ID: 10351), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 198 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Arg, Tyr, Ser) have been reported in individuals with hemophilia A (Elmahmoudi 2012, Lu 2018, Rydz 2013). Based on available information, the p.Cys198Gly variant is considered to be likely pathogenic. References: Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat. 2005;26(3):249-254. Elmahmoudi H et al. First report of molecular diagnosis of Tunisian hemophiliacs A: identification of 8 novel causative mutations. Diagn Pathol. 2012;7:93. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018;24(2):291-298. Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008;93(5):722-728. 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;15(4):932-941. Mazurier C et al. Factor VIII deficiency not induced by FVIII gene mutation in a female first cousin of two brothers with haemophilia A. Br J Haematol. 2002;119(2):390-392. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013;88(12):1030-1034. References: Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with severe hemophilia A. Hum Mutat. 2005;26(3):249-254. Elmahmoudi H et al. First report of molecular diagnosis of Tunisian hemophiliacs A: identification of 8 novel causative mutations. Diagn Pathol. 2012;7:93. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018;24(2):291-298. Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008;93(5):722-728. 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;15(4):932-941. Mazurier C et al. Factor VIII deficiency not induced by FVIII gene mutation in a female first cousin of two brothers with haemophilia A. Br J Haematol. 2002;119(2):390-392. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013;88(12):1030-1034. |
| OMIM | RCV000011064 | SCV000031291 | pathogenic | Hereditary factor VIII deficiency disease | 2002-11-01 | no assertion criteria provided | literature only |