ClinVar Miner

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

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Total submissions: 4
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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 RCV000508201 SCV000603514 pathogenic not specified 2017-03-07 criteria provided, single submitter clinical testing
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

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