ClinVar Miner

Submissions for variant NM_000132.3(F8):c.1172G>A (p.Arg391His) (rs28935499)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757254 SCV000885404 pathogenic Hereditary factor VIII deficiency disease 2019-04-16 criteria provided, single submitter clinical testing The F8 c.1172G>A; p.Arg391His variant (rs28935499), also known as p.Arg372His for legacy nomenclature, has been described in several individuals affected with hemophilia A (see link to factor VIII database and references therein). It is reported in Clinvar (Variation ID: 10111) and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 391 is conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant to be deleterious. In vitro functional studies of this variant protein demonstrate a significant reduction in thrombin-catalyzed activation and function (Nogami 2005). Additionally, other variants at this codon (p.Arg391Pro, p.Arg391Leu) have been observed in individuals affected with hemophilia A and are considered pathogenic (see link to factor VIII database and references therein). Based on available information, this variant is considered pathogenic. References: Link to Factor 8 database: Nogami K et al. Thrombin-catalyzed activation of factor VIII with His substituted for Arg372 at the P1 site. Blood. 2005;105(11):4362-8.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852002 SCV000899444 pathogenic Hereditary factor IX deficiency disease 2019-02-01 criteria provided, single submitter research
OMIM RCV000010823 SCV000031050 pathogenic FACTOR VIII (OKAYAMA) 1989-10-01 no assertion criteria provided literature only

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