ClinVar Miner

Submissions for variant NM_000132.4(F8):c.6977G>A (p.Arg2326Gln)

gnomAD frequency: 0.00001  dbSNP: rs137852360
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851861 SCV000899878 pathogenic Hereditary factor IX deficiency disease 2019-02-01 criteria provided, single submitter research
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV001169905 SCV001251852 likely pathogenic not provided 2020-05-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000010839 SCV001472725 pathogenic Hereditary factor VIII deficiency disease 2019-11-06 criteria provided, single submitter clinical testing The F8 c.6977G>A; p.Arg2326Gln variant (rs137852360), also known as R2307Q, is reported in the literature in multiple individuals affected with mild to moderate hemophilia A (see link to FVIII Database and references therein). This variant is reported in ClinVar (Variation ID: 10126), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 2326 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate destabilization of the protein (Spiegel 2004). Additionally, other amino acid substitutions at this codon (Gly, Leu, Pro) have been reported in individuals with moderate to severe hemophilia A and are considered pathogenic (see link to FVIII Database and references therein). Based on available information, this variant is considered to be pathogenic. References: Link to Factor VIII Gene Database: http://f8-db.eahad.org/index.php Spiegel PC et al. Surface-exposed hemophilic mutations across the factor VIII C2 domain have variable effects on stability and binding activities. J Biol Chem. 2004 Dec 17;279(51):53691-8.
Genetics and Molecular Pathology, SA Pathology RCV000010839 SCV002556373 likely pathogenic Hereditary factor VIII deficiency disease 2020-04-08 criteria provided, single submitter clinical testing PS1, PM1, PP3, PP5.
OMIM RCV000010839 SCV000031066 pathogenic Hereditary factor VIII deficiency disease 1985-05-30 no assertion criteria provided literature only

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