ClinVar Miner

Submissions for variant NM_000132.3(F8):c.902G>A (p.Arg301His) (rs137852403)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255290 SCV000322264 pathogenic not provided 2016-08-19 criteria provided, single submitter clinical testing The R301H pathogenic variant in the F8 gene has been frequently reported in patients with severe hemophilia A (Higuchi et al., 1991). The R301H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R301H variant is a conservative amino acid substitution. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same codon (R301S, R301G, R301C, R301P, R301L) and in nearby residues (L296F, V297M, V297A, V297G, R298T, N299I, H300D, H300L, H300P, A303P, A303E, S304P, L305S) have been reported in the Human Gene Mutation Database in association with hemophilia A (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R301H as a pathogenic variant
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000255290 SCV000883833 pathogenic not provided 2018-01-16 criteria provided, single submitter clinical testing The F8 c.902G>A; p.Arg301His variant (rs137852403), also known as R282H for legacy nomenclature, is reported in the literature in patients with severe hemophilia (Casana2008, Factor VIII database). This variant is also reported in the ClinVar database (Variation ID: 10192). This variant is not found in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 301 is highly conserved and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this missense variant to be damaging. Based on the above information, we consider this variant to be pathogenic. References: Factor VIII database: Casana P et al. Severe and moderate hemophilia A: identification of 38 new genetic alterations. Haematologica 2008; 93:1091-1094.
OMIM RCV000010905 SCV000031132 pathogenic Hereditary factor VIII deficiency disease 1993-11-01 no assertion criteria provided literature only

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