Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001802265 | SCV002050033 | pathogenic | Hereditary factor VIII deficiency disease | 2020-12-17 | criteria provided, single submitter | clinical testing | The F8 c.760A>G; p.Asn254Asp variant is reported in the literature in multiple individuals affected with severe hemophilia A (see F8 database and references therein). Functional analyses demonstrate that individuals with this variant have factor VIII activity of <1% (F8 database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (p.Asn254Tyr, p.Asn254Ile, p.Asn254Ser and p.Asn254Thr) have been reported in individuals with severe hemophilia A and are considered pathogenic (Bicocchi 2003, Gouw 2011, Green 2008, Reitter 2010). The asparagine at codon 254 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.908). Based on available information, this variant is considered to be pathogenic. References: F8 variant database: https://f8-db.eahad.org/ Bicocchi MP et al. Analysis of 18 novel mutations in the factor VIII gene. Br J Haematol. 2003 Sep;122(5):810-7. Gouw SC et al. Influence of the type of F8 gene mutation on inhibitor development in a single centre cohort of severe haemophilia A patients. Haemophilia. 2011 Mar;17(2):275-81. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. Reitter S et al. Austrian Molecular Haemophilia Study Group. Spectrum of causative mutations in patients with haemophilia A in Austria. Thromb Haemost. 2010 Jul;104(1):78-85. |