Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001001162 | SCV001158313 | likely pathogenic | Hereditary factor VIII deficiency disease | 2019-04-09 | criteria provided, single submitter | clinical testing | The F8 c.1538-18G>A variant (also known as IVS 10-18 G>A), to our knowledge, has only been reported in individuals with mild/moderate hemophilia A who are of Italian decent (Bach 2015, Castaman 2009, Prejano 2015, Santacroce 2008a and 2008b). Santacroce et al. describe all patients in their study as sharing a common haplotype; however, Bach et al. reports a patient who does not share this same haplotype. mRNA analysis of the variant shows a lack of the first 36 nucleotides of exon 11 resulting in an in-frame deletion of the first 12 amino acids in exon 11 (Castaman 2010), presumably due to preferential usage of an internal acceptor site at this location. This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Bach JE et al. Identification of deep intronic variants in 15 haemophilia A patients by next generation sequencing of the whole factor VIII gene. Thromb Haemost. 2015 Oct;114(4):757-67. Castaman G et al. F8 mRNA studies in haemophilia A patients with different splice site mutations. Haemophilia. 2010 Sep 1;16(5):786-90. Castaman G et al. Molecular and phenotypic determinants of the response to desmopressin in adult patients with mild hemophilia A. J Thromb Haemost. 2009 Nov;7(11):1824-31. Prejano S et al. Prevalence of IVS10nt-18G/A in Calabrian patients with moderate/mild hemophilia A and relation with Factor VIII inhibitor antibodies. Blood Coagul Fibrinolysis. 2015 Oct;26(7):750-4. 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. 2008a;53(3):275-84. Santacroce R et al. Screening of mutations of hemophilia A in 40 Italian patients: a novel G-to-A mutation in intron 10 of the F8 gene as a putative cause of mild hemophilia A in southern Italy. Blood Coagul Fibrinolysis. 2008b Apr;19(3):197-202. |
| ISTH- |
RCV001001162 | SCV002515617 | likely pathogenic | Hereditary factor VIII deficiency disease | no assertion criteria provided | research |