Submissions for variant NM_000132.4(F8):c.6506G>A (p.Arg2169His)

dbSNP: rs137852461

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003147281	SCV000885397	pathogenic	not provided	2023-02-13	criteria provided, single submitter	clinical testing	The F8 c.6506G>A; p.Arg2169His variant (rs137852461), also known as Arg2150His, is reported in the literature in individuals with mild to moderate hemophilia A (see F8 database and references therein, Bogdanova 2007, Diamond 1992, Green 2008, Higuchi 1991, Suzuki 2018). This variant is reported in ClinVar (Variation ID: 10315) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2169 is highly conserved and computational analyses predict that this variant is deleterious (REVEL: 0.964). Based on available information, this variant is considered to be pathogenic. References: Link to F8 database: http://www.factorviii-db.org/ Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. 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. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. 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. Suzuki et al. Combined deficiency of factors V and VIII by chance coinheritance of parahaemophilia and haemophilia A, but not by mutations of either LMAN1 or MCFD2, in a Japanese family. Haemophilia. 2018 Jan;24(1):e13-e16.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851846	SCV000899847	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
Revvity Omics, Revvity	RCV003147281	SCV002022269	pathogenic	not provided	2019-09-27	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000011028	SCV002556422	pathogenic	Hereditary factor VIII deficiency disease	2021-05-14	criteria provided, single submitter	clinical testing
GeneDx	RCV003147281	SCV005201770	pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a reduction of factor VIII levels and activity in addition to impaired binding to VWF (Jacquemin et al., 2000; van den Biggelarr et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R2150H); This variant is associated with the following publications: (PMID: 19473423, 34708896, 35014236, 18691168, 32589464, 21883705, 16972227, 20800587, 19719828, 18387975, 1908096, 29082580, 30046696, 31064749, 18565236, 17610549, 17445092, 17222201, 16769589, 16173970, 12871415, 11857744, 11442643, 11341489, 10910910, 10896236, 10404764, 10338101, 1301932, 33245802, 33706050, 32897612, 15921397, 21909383)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000011028	SCV005416630	pathogenic	Hereditary factor VIII deficiency disease		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4+PP4+PP3_Strong
Fulgent Genetics, Fulgent Genetics	RCV005049328	SCV005683144	pathogenic	Hereditary factor VIII deficiency disease; Thrombophilia, X-linked, due to factor 8 defect	2024-05-03	criteria provided, single submitter	clinical testing
OMIM	RCV000011028	SCV000031255	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	RCV000011028	SCV001424858	pathogenic	Hereditary factor VIII deficiency disease	2019-06-01	no assertion criteria provided	clinical testing