Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000010797 | SCV004363662 | pathogenic | Hereditary factor VIII deficiency disease | 2024-02-02 | reviewed by expert panel | curation | The c.6976C>T (p.Arg2326Ter) creates a premature stop codon in exon 26, which is the last exon of the F8 gene. Therefore, protein is not expected to undergo NMD and meets PVS1_Strong. This variant is completely absent from gnomAD v2.1.1 and v3.1.1, which meets PM2_Supporting. More than 20 patients are reported in the literature with severe/moderate hemophilia A, meeting F8 phenotype criteria for PS4_Very strong and PP4_Moderate. The variant was also reported in two affected brothers and their carrier mother, which meets criteria for PP1 (PMID: 2987704). There is also at least one report of a de novo case where maternity was not confirmed, meeting PS2_Moderate (PMID: 2104741). In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F9: PVS1_Strong, PS4_Very strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP1. |
| ARUP Laboratories, |
RCV000010797 | SCV002048190 | pathogenic | Hereditary factor VIII deficiency disease | 2021-01-08 | criteria provided, single submitter | clinical testing | The F8 c.6976C>T; p.Arg2326Ter variant (rs137852354), also known as p.Arg2307Ter, is reported in the literature in numerous individuals affected with severe hemophilia A and several individuals with mild-to-moderate hemophilia (Becker 1996, Gitschier 1985, Higuchi 1989, Higuchi 1991, Hill 2005, Hua 2010, Jayandharan 2009, Levinson 1990, Millar 1991, Nair 2016, Factor VIII database). The p.Arg2326Ter variant cosegregates with affected individuals in at least one family (Gitschier 1985) and has been reported as a de novo variant in another case (Levinson 1990). This variant is reported in ClinVar (Variation ID: 10085) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the F8 gene. While this may not lead to nonsense-mediated decay, it is predicted to produce a truncated protein lacking 26 amino acids, many of which exhibit pathogenic missense variants and thus are likely to be functionally important. Based on available information, the p.Arg2326Ter variant is considered to be pathogenic. References: Factor VIII database: http://www.factorviii-db.org/ 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. Gitschier J et al. Detection and sequence of mutations in the factor VIII gene of haemophiliacs. Nature. 1985 May 30-Jun 5;315(6018):427-30. Higuchi M et al. Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7405-9. Higuchi M et al. Molecular defects in hemophilia A: identification and characterization of mutations in the factor VIII gene and family analysis. Blood. 1989 Aug 15;74(3):1045-51. Hill M et al. Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype. Haemophilia. 2005 Mar;11(2):133-41. Hua BL et al. Identification of seven novel mutations in the factor VIII gene in 18 unrelated Chinese patients with hemophilia A. Chin Med J (Engl). 2010 Feb 5;123(3):305-10. Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. Levinson B et al. Molecular analysis of hemophilia A mutations in the Finnish population. Am J Hum Genet. 1990 Jan;46(1):53-62. Millar DS et al. The molecular genetics of haemophilia A: screening for point mutations in the factor VIII gene using the restriction enzyme TaqI. Hum Genet. 1991 Sep;87(5):607-12. Nair PS et al. Factor VIII Antigen, Activity, and Mutations in Hemophilia A. Clin Appl Thromb Hemost. 2016 May;22(4):381-5. |
| Genetics and Molecular Pathology, |
RCV000010797 | SCV002556607 | pathogenic | Hereditary factor VIII deficiency disease | 2020-03-20 | criteria provided, single submitter | clinical testing | PVS1, PM2, PP4, PP5 |
| OMIM | RCV000010797 | SCV000031024 | pathogenic | Hereditary factor VIII deficiency disease | 1988-09-01 | no assertion criteria provided | literature only |