Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001286245 | SCV001472780 | likely pathogenic | Hereditary factor VIII deficiency disease | 2020-07-28 | criteria provided, single submitter | clinical testing | The F8 c.640T>G; p.Phe214Val variant, also known in traditional nomenclature as p.Phe195Val, is reported in the literature in an individual affected with mild hemophilia A and F8 activity measured at 16 IU/dL (Waseem 1999). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The phenylalanine at codon 214 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Phe214Cys, p.Phe214Leu, p.Phe214Ser) have been reported in individuals with mild to moderate hemophilia A and are considered disease-causing (Margaglione 2008, Miller 2012, Seary 2012). Based on available information, the p.Phe214Val variant is considered to be likely pathogenic. References: Margaglione M et al. The Italian AICE-Genetics hemophilia A database: results and correlation with clinical phenotype. Haematologica. 2008;93(5):722-728. Miller CH et al. F8 and F9 mutations in US haemophilia patients: correlation with history of inhibitor and race/ethnicity. Haemophilia. 2012;18(3):375-382. Seary ME et al. DDAVP responsiveness in children with mild or moderate haemophilia A correlates with age, endogenous FVIII:C level and with haemophilic genotype. Haemophilia. 2012;18(1):50-55. Waseem NH et al. Start of UK confidential haemophilia A database: analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Haemophilia Centres. Thromb Haemost. 1999;81(6):900-905. |