ClinVar Miner

Submissions for variant NM_000132.4(F8):c.1172G>A (p.Arg391His)

dbSNP: rs28935499
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Total submissions: 5
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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: http://www.factorviii-db.org/ 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
Genetics and Molecular Pathology, SA Pathology RCV000757254 SCV002761397 pathogenic Hereditary factor VIII deficiency disease 2019-11-05 criteria provided, single submitter clinical testing
GeneDx RCV004812295 SCV005437429 pathogenic not provided 2024-06-11 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 p.(R372H); This variant is associated with the following publications: (PMID: 33245802, 33706050, 32897612, 33760382, 34844950, 28056528, 33314404, 17901109, 21883705, 17610560, 31829478, 25955082, 19302446, 32384547, 32232366, 36696222, 8449505, 18691168, 18565236, 16972227, 12871415, 9886318, 1349567, 1973901, 19473423, 2498882, 32166871, 12325022, 16128892, 29296726, 18387975, 31064749, 38068488, 15705787, 23711237)
OMIM RCV000010823 SCV000031050 pathogenic FACTOR VIII (OKAYAMA) 1989-10-01 no assertion criteria provided literature only

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