Submissions for variant NM_000132.4(F8):c.6545G>A (p.Arg2182His)

dbSNP: rs137852466

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000011033	SCV001473198	pathogenic	Hereditary factor VIII deficiency disease	2021-05-18	criteria provided, single submitter	clinical testing	The F8 c.6545G>A; p.Arg2182His variant (rs137852466), also known as p.Arg2163His, is reported in the literature in multiple individuals affected with moderate to severe hemophilia A (see link to Factor VIII database and references therein; Jayandharan 2017, Johnsen 2017, Tuddenham 1994). This variant is reported in ClinVar (Variation ID: 10320), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2182 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (c.6544C>T; p.Arg2182Cys, c. 6544C>G; p.Arg2182Gly) have been reported in individuals with severe hemophilia A and are considered pathogenic (see link to Factor VIII database, Jayandharan 2009). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org Jayandharan GR et al. Polymorphism in factor VII gene modifies phenotype of severe haemophilia. Haemophilia. 2009 Nov;15(6):1228-36. Johnsen JM et al. Novel approach to genetic analysis and results in 3000 hemophilia patients enrolled in the My Life, Our Future initiative. Blood Adv. 2017 May 18;1(13):824-834. Tuddenham EG et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene, second edition. Nucleic Acids Res. 1994 Nov 11;22(22):4851-68.
Genetics and Molecular Pathology, SA Pathology	RCV000011033	SCV002761416	pathogenic	Hereditary factor VIII deficiency disease	2021-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011033	SCV005204121	pathogenic	Hereditary factor VIII deficiency disease	2024-06-21	criteria provided, single submitter	clinical testing	Variant summary: F8 c.6545G>A (p.Arg2182His) results in a non-conservative amino acid change located in the coagulation factor 5/8 C-terminal domain (IPR000421) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183342 control chromosomes. c.6545G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (e.g.Miller_2012, Eckhardt_2013, Azadmehr_2021) . These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 35014236, 23926300, 22103590). ClinVar contains an entry for this variant (Variation ID: 10320). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV004821959	SCV005442886	pathogenic	not provided	2024-07-02	criteria provided, single submitter	clinical testing	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 Arg2163His; This variant is associated with the following publications: (PMID: 35014236, 7937051, 7984443, 29490426, 32190902, 36595620, 33245802, 33706050, 24845853, 10215414, 36983317, 9829908, 38196513, 34844950, 32224444, 19473423, 34272389, 34788507, 34708896, 32897612, 9569189, 10404764, 11341489, 11554935, 15710596, 15810915, 16086318)
OMIM	RCV000011033	SCV000031260	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	RCV000011033	SCV001424863	pathogenic	Hereditary factor VIII deficiency disease	2019-06-01	no assertion criteria provided	clinical testing