Submissions for variant NM_000132.4(F8):c.6533G>A (p.Arg2178His)

gnomAD frequency: 0.00001  dbSNP: rs137852465

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852179	SCV000899851	likely pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114184	SCV003799294	pathogenic	not provided	2023-10-09	criteria provided, single submitter	clinical testing	The F8 c.6533G>A; p.Arg2178His variant (rs137852465) is reported in the literature in multiple individuals affected with mild hemophilia A (see link to FVIII database and references therein). This variant is also reported in ClinVar (Variation ID: 10319). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2178 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.82). Additionally, other variants at this codon (c.6532C>T, p.Arg2178Cys; c.6533G>T, p.Arg2178Leu) have been reported in individuals with mild to moderate hemophilia A and are considered pathogenic (FVIII database). Based on available information, the p.Arg2178His variant is considered to be pathogenic. References: Link to FVIII database: http://www.factorviii-db.org/
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011032	SCV005381270	pathogenic	Hereditary factor VIII deficiency disease	2024-08-07	criteria provided, single submitter	clinical testing	Variant summary: F8 c.6533G>A (p.Arg2178His) results in a non-conservative amino acid change located in the Coagulation factor 5/8, C-terminal domain (IPR000421) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 183351 control chromosomes. c.6533G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A) (Examples: Green_2008 and Miller_2022). 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: 18691168, 22103590). ClinVar contains an entry for this variant (Variation ID: 10319). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000011032	SCV000031259	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000011032	SCV002515602	likely pathogenic	Hereditary factor VIII deficiency disease		no assertion criteria provided	research