ClinVar Miner

Submissions for variant NM_000132.3(F8):c.1834C>T (p.Arg612Cys) (rs137852428)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413577 SCV000491183 pathogenic not provided 2018-04-16 criteria provided, single submitter clinical testing The R612C variant in the F8 gene has been reported previously, using alternate nomenclature R593C, in association with Hemophilia A (for examples, see Higuchi et al., 1991; Pieneman et al., 1995; Bicocchi et al., 2005; Trampus Bakija et al., 2015). Functional studies show R612C reduces factor VIII activity, and leads to intracellular accumulation and subsequent degradation of the F8 protein (Roelse et al., 2000). The R612C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. A missense variant at the same residue (R612P) has been reported in the Human Gene Mutation Database in association with Hemophilia A (Owaidah et al., 2009; Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence, we interpret R612C as a pathogenic variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000010949 SCV000603514 pathogenic Hereditary factor VIII deficiency disease 2018-11-06 criteria provided, single submitter clinical testing The F8 c.1834C>T; p.Arg612Cys variant (rs137852428), also known as Arg593Cys, is reported in multiple patients associated with mild or moderate hemophilia (Antonarakis 1995, Diamond 1992, Higuchi 1991, Markoff 2009, Trampus Bajika 2015, Factor VIII variant database). This variant is reported as pathogenic in ClinVar (Variation ID: 10236), and found in the general Latino population with an allele frequency of 0.02% (4/26578 alleles, including 3 hemizygotes) in the Genome Aggregation Database. The arginine at codon 612 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Factor VIII variant database: Antonarakis SE et al. Molecular etiology of factor VIII deficiency in hemophilia A. Hum Mutat. 1995;5(1):1-22. Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992;1(3):248-57. 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. 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 Jul;15(4):932-41. Trampus Bakija A et al. Specific and global coagulation tests in patients with mild haemophilia A with a double mutation (Glu113Asp, Arg593Cys). Blood Transfus. 2015 Oct;13(4):622-30.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851933 SCV000899317 pathogenic Hereditary factor IX deficiency disease 2019-02-01 criteria provided, single submitter research
OMIM RCV000010949 SCV000031176 pathogenic Hereditary factor VIII deficiency disease 1995-01-01 no assertion criteria provided literature only

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.