Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001802513 | SCV002048741 | likely pathogenic | Hereditary factor VIII deficiency disease | 2020-12-24 | criteria provided, single submitter | clinical testing | The F8 c.2101A>G; p.Met701Val variant is reported in the literature in multiple individuals affected with mild hemophilia A (see F8 database and references therein, Rydz 2013). In vitro functional analyses demonstrate that individuals with this variant have factor VIII activity between 15-27% (F8 database, Rydz 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 701 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.549). Additionally, other amino acid substitutions at this codon (Thr, Leu, Ile) have been reported in individuals with mild hemophilia A and are considered pathogenic (Johnsen 2017, Rydz 2013). Based on available information, the p.Met701Val variant is considered to be likely pathogenic. References: F8 Database: https://f8-db.eahad.org/ 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. Rydz N et al. The Canadian "National Program for hemophilia mutation testing" database: a ten-year review. Am J Hematol. 2013 Dec;88(12):1030-4. |