Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001002670 | SCV001160658 | pathogenic | Hereditary factor VIII deficiency disease | 2019-06-28 | criteria provided, single submitter | clinical testing | The F8 c.302A>G; p.Asp101Gly variant, also known as p.Asp82Gly, is reported in the literature in several individuals affected with hemophilia A, including at least one with <1% normal clotting activity (Liu 1998, Johnsen 2017). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartate at codon 101 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Asp101His, p.Asp101Val) have been reported in individuals with hemophilia A and are considered disease-causing (Becker 1996, Johnsen 2017, Leuer 2011). Based on available information, the p.Asp101Gly variant is considered to be pathogenic. References: Becker J et al. Characterization of the factor VIII defect in 147 patients with sporadic hemophilia A: family studies indicate a mutation type-dependent sex ratio of mutation frequencies. Am J Hum Genet. 1996 Apr;58(4):657-70. 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. Leuer M et al. Somatic mosaicism in hemophilia A: a fairly common event. Am J Hum Genet. 2001 Jul;69(1):75-87. Liu M et al. A domain mutations in 65 haemophilia A families and molecular modelling of dysfunctional factor VIII proteins. Br J Haematol. 1998 Dec;103(4):1051-60. |