Submissions for variant NM_000132.4(F8):c.5122C>T (p.Arg1708Cys)

gnomAD frequency: 0.00001  dbSNP: rs111033613

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001092277	SCV001248698	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000010826	SCV001370095	pathogenic	Hereditary factor VIII deficiency disease	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PP3,PP5.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000010826	SCV002048842	pathogenic	Hereditary factor VIII deficiency disease	2020-11-20	criteria provided, single submitter	clinical testing	The F8 c.5122C>T; p.Arg1708Cys variant (rs111033613), also known as Arg1689Cys, is reported in the literature in multiple individuals affected with moderate hemophilia A (see link to Factor VIII database and references therein). This variant is reported in ClinVar (Variation ID: 10114), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 1708 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.941). The arginine residue at this position is critical for the thrombin-mediated cleavage required to generate an activated F8 fragment (Pittman 1988), and p.Arg1708Cys variant prevents the processing of the F8 protein into the activated form (Arai 1990, Kamisue 1994). Additionally, other amino acid substitutions at this codon (p.Arg1708Ser, p.Arg1708His, p.Arg1708Leu) have been reported in individuals with hemophilia A and are considered pathogenic (Factor VIII database and references therein). Based on available information, this variant is considered to be pathogenic. References: Factor VIII variant database: http://f8-db.eahad.org/index.php Arai M et al. Characterization of a thrombin cleavage site mutation (Arg 1689 to Cys) in the factor VIII gene of two unrelated patients with cross-reacting material-positive hemophilia A. Blood. 1990 75(2):384-9. Kamisue S et al. Abnormal factor VIII Hiroshima: defect in crucial proteolytic cleavage by thrombin at Arg1689 detected by a novel ELISA. Br J Haematol. 1994 86(1):106-11. Pittman D et al. Proteolytic requirements for thrombin activation of anti-hemophilic factor (factor VIII). Proc Natl Acad Sci U S A. 1988 85(8):2429-33.
OMIM	RCV000010826	SCV000031053	pathogenic	Hereditary factor VIII deficiency disease	1992-05-01	no assertion criteria provided	literature only
OMIM	RCV000010827	SCV000031054	pathogenic	FACTOR VIII (EAST HARTFORD)	1992-05-01	no assertion criteria provided	literature only
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000010826	SCV001424879	pathogenic	Hereditary factor VIII deficiency disease	2019-06-01	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001092277	SCV001926361	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001092277	SCV001952184	pathogenic	not provided		no assertion criteria provided	clinical testing