ClinVar Genomic variation as it relates to human health

The F8 c.6547A>G; p.Met2183Val variant, also known as Met2164Val for legacy nomenclature, is reported in the literature in individuals with mild hemophilia A (Eckhardt 2013, Laurie 2007, Markoff 2009, Tavassoli 1998, Waseem 1999), with one observation of the variant occurring de novo (Tavassoli 1998). This variant is reported in ClinVar (Variation ID: 626933). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 2183 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two different variants at this codon (Met2183Lys/M2164K, Met2183Arg/M2164R) are also reported in individuals with hemophilia A (Eckhardt 2013, Liu 2000, Markoff 2009), further supporting the importance of this residue for protein structure/function. Based on available information, this variant is considered to be pathogenic. REFERENCES Eckhardt CL et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A. Blood. 2013 Sep 12;122(11):1954-62. Laurie AD et al. The molecular aetiology of haemophilia A in a New Zealand patient group. Haemophilia. 2007 Jul;13(4):420-7. Liu ML et al. Hemophilic factor VIII C1- and C2-domain missense mutations and their modeling to the 1.5-angstrom human C2-domain crystal structure. Blood. 2000 Aug 1;96(3):979-87. Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 Jul;15(4):932-41. Tavassoli K et al. Molecular diagnostics of 15 hemophilia A patients: characterization of eight novel mutations in the factor VIII gene, two of which result in exon skipping. Hum Mutat. 1998;12(5):301-3. Waseem NH et al. Start of UK confidential haemophilia A database: analysis of 142 patients by solid phase fluorescent chemical cleavage of mismatch. Haemophilia Centres. Thromb Haemost. 1999 Jun;81(6):900-5.

The F8 c.6547A>G variant is classified as Likely Pathogenic (PS4_Moderate, PM1_Supporting, PM2, PM5, PP3) The F8 c.6547A>G variant is a single nucleotide change in exon 23/26 of the F8 gene, which is predicted to change the amino acid methionine at position 2183 in the protein to valine. The variant has been reported in probands with a clinical presentation of OMIM:306700 ( Has been reported in unrelated individuals with mild haemophilia A. PMID:23926300, PMID 19473423. Supplementary papers for both publications. ) (PS4_Moderate). This variant is absent from population databases (PM2). This variant is located in the conserved PMID:10910913 protein modelling ( PMID:10910913 protein modelling ) (PM1_supporting). PMID:10910913 - the variant is expected to disrupt the core structure, affecting protein structure/function This variant is a novel missense change at an amino acid residue where a different missense change has been seen before (Missing PM5 Note) (PM5). Computational predictions support a deleterious effect on the gene or gene product (PP3). Additionally, two different variants at this codon (Met2183Lys/M2164K, Met2183Arg/M2164R) are also reported in individuals with hemophilia A (Eckhardt 2013, Liu 2000, Markoff 2009), further supporting the importance of this residue for protein structure/function The variant has been reported in dbSNP (rs781797728) and in the HGMD database: CM980716. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 626933).

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23926300, 10910913, 10404764, 7579394, 36007526, 19473423, 17901109, 9792405, 17610560, 30046696, 31064749)