Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001002324 | SCV001160218 | likely pathogenic | Hereditary factor VIII deficiency disease | 2019-01-11 | criteria provided, single submitter | clinical testing | The F8 c.5527G>A; p.Ala1843Thr variant is reported in the literature in several individuals affected with mild hemophilia A (Casana 2008, Fernandez-Lopez 2005, Factor VIII database). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 1843 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon or adjacent codons (p.Met1842Ile, p.Ala1843Val, p.Pro1844Leu, p.Pro1844Ser) have been reported in individuals with hemophilia A and are considered pathogenic (Fernandez-Lopez 2005, Guillet 2006, Higuchi 1991, Lin 2008). Based on available information, this variant is considered to be likely pathogenic. References: Factor VIII database: http://www.factorviii-db.org/ Casana P et al. Founder haplotype associated with the factor VIII Asp1241Glu polymorphism in a cohort of mild hemophilia A patients. J Thromb Haemost. 2008 Aug;6(8):1428-30. Fernandez-Lopez O et al. The spectrum of mutations in Southern Spanish patients with hemophilia A and identification of 28 novel mutations. Haematologica. 2005 May;90(5):707-10. Guillet B et al. Detection of 95 novel mutations in coagulation factor VIII gene F8 responsible for hemophilia A: results from a single institution. Hum Mutat. 2006 Jul;27(7):676-85. Higuchi M et al. Molecular characterization of mild-to-moderate hemophilia A: detection of the mutation in 25 of 29 patients by denaturing gradient gel electrophoresis. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8307-11. Lin SY et al. Mutation spectrum of 122 hemophilia A families from Taiwanese population by LD-PCR, DHPLC, multiplex PCR and evaluating the clinical application of HRM. BMC Med Genet. 2008 Jun 20;9:53. doi: 10.1186/1471-2350-9-53. |