Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001285215 | SCV001471613 | likely pathogenic | Hereditary factor VIII deficiency disease | 2020-07-29 | criteria provided, single submitter | clinical testing | The F8 c.403G>T; p.Asp135Tyr variant, also known as Asp116Tyr, is reported in the literature in multiple individuals affected with severe hemophilia A (Leuer 2001, Markoff 2009, Repesse 2007, Santacroce 2008). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartic acid at codon 135 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (Gly, Glu, Asn) have been reported in individuals with severe hemophilia A (Lin 2008, Markoff 2009). Based on available information, the p.Asp135Tyr variant is considered to be likely pathogenic. References: Leuer M et al. Somatic mosaicism in hemophilia A: a fairly common event. Am J Hum Genet. 2001;69(1):75-87. 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;9:53. 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;15(4):932-941. Repesse Y et al. Factor VIII (FVIII) gene mutations in 120 patients with hemophilia A: detection of 26 novel mutations and correlation with FVIII inhibitor development. J Thromb Haemost. 2007;5(7):1469-1476. Santacroce R et al. Identification of 217 unreported mutations in the F8 gene in a group of 1,410 unselected Italian patients with hemophilia A. J Hum Genet. 2008;53(3):275-284. |