Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
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: http://www.factorviii-db.org 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 | |
Prevention |
RCV004745151 | SCV005360607 | pathogenic | F8-related disorder | 2024-08-10 | no assertion criteria provided | clinical testing | The F8 c.902G>A variant is predicted to result in the amino acid substitution p.Arg301His. This variant is also described using legacy nomenclature as p.Arg282His, has been reported in many individuals with moderate to severe hemophilia A (Higuchi et al. 1991. PubMed ID: 1908096; F8 Database: http://www.factorviii-db.org/advance_search_results.php). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. |