Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001802578 | SCV002048948 | pathogenic | Hereditary factor VIII deficiency disease | 2020-12-30 | criteria provided, single submitter | clinical testing | The F8 c.4758G>A; p.Trp1586Ter variant is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (see F8 database and references therein, Pinto 2016, Villarreal-Martinez 2020). In vitro functional analyses demonstrate that individuals with this variant have factor VIII activity of <5% (F8 database, Pinto 2016, Villarreal-Martinez 2020). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, another nonsense variant at this codon (c.4757G>A, p.Trp1586Ter) has been reported in individuals with severe hemophilia A and is considered pathogenic (F8 database, Laurie 2007). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: F8 variant database link: https://f8-db.eahad.org/ Laurie AD et al. The molecular aetiology of haemophilia A in a New Zealand patient group. Haemophilia. 2007 Jul;13(4):420-7. Pinto P et al. F8 gene mutation profile in Indian hemophilia A patients: Identification of 23 novel mutations and factor VIII inhibitor risk association. Mutat Res. 2016 Apr;786:27-33. Villarreal-Martinez L et al. Molecular genetic diagnosis by next-generation sequencing in a cohort of Mexican patients with haemophilia and report of novel variants. Blood Cells Mol Dis. 2020 Jul;83:102423. |