Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001287862 | SCV001474603 | likely pathogenic | Hereditary factor VIII deficiency disease | 2019-10-22 | criteria provided, single submitter | clinical testing | The F8 c.1825A>C; p.Asn609His variant (also known as Asn590His for legacy nomenclature), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 609 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Three additional variants at this codon (Asn609Lys, Asn609Ile, Asn609Tyr) are reported in individuals with moderate or severe hemophilia A (Dai 2012, Johnsen 2017, Liu 2002, Markoff 2009, Ravanbod 2012, see F8 database), indicating the importance of this residue. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Link to F8 Variant Database: http://f8-db.eahad.org/advance_search_results.php Dai J et al. The status of carrier and prenatal diagnosis of haemophilia in China. Haemophilia. 2012 Mar;18(2):235-40. 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. Liu ML et al. Non-inversion factor VIII mutations in 80 hemophilia A families including 24 with alloimmune responses. Thromb Haemost. 2002 Feb;87(2):273-6. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. Ravanbod S et al. Identification of 123 previously unreported mutations in the F8 gene of Iranian patients with haemophilia A. Haemophilia. 2012 May;18(3):e340-6. |