Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001000840 | SCV001157911 | pathogenic | Hereditary factor VIII deficiency disease | 2018-10-11 | criteria provided, single submitter | clinical testing | The F8 c.5999G>T; p.Gly2000Val variant, is reported in the literature in at least one individual affected with severe hemophilia A (You 2010). This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 2000 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Other computational analyses (Alamut v.2.11) predict that this variant may impact splicing weakening the nearby canonical acceptor splice site. Additionally, other amino acid substitutions at this codon (Ala, Arg, Asp, Ser) have been reported in individuals with severe hemophilia and are considered pathogenic (Awidi 2010, Goodeve 2000, Lu 2018, Santacroce 2008, Factor VIII database and references therein). Based on available information, the p.Gly2000Val variant is considered to be pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org/ Awidi A et al. Study of mutations in Jordanian patients with haemophilia A: identification of five novel mutations. Haemophilia. 2010 Jan;16(1):136-42. Goodeve AC et al. Relationship between factor VIII mutation type and inhibitor development in a cohort of previously untreated patients treated with recombinant factor VIII (Recombinate). Recombinate PUP Study Group. Thromb Haemost. 2000 Jun;83(6):844-8. Lu Y et al. Spectrum and origin of mutations in sporadic cases of haemophilia A in China. Haemophilia. 2018 Mar;24(2):291-298. Santacroce R et al. Identification of 217 unreported mutations in the F8 gene in a group of 1,410 unselected Italian patients with hemophilia A. J Hum Genet. 2008;53(3):275-84. You CW et al. Mutation analysis of factor VIII in Korean patients with severe hemophilia A. Int J Hematol. 2010 Jun;91(5):784-91. |