Submissions for variant NM_000132.4(F8):c.6547A>G (p.Met2183Val)

dbSNP: rs781797728

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851608	SCV000899360	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001286233	SCV001472766	pathogenic	Hereditary factor VIII deficiency disease	2019-12-04	criteria provided, single submitter	clinical testing	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.
CeGaT Center for Human Genetics Tuebingen	RCV001310761	SCV001500685	pathogenic	not provided	2021-01-01	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV001286233	SCV002761590	likely pathogenic	Hereditary factor VIII deficiency disease	2022-05-30	criteria provided, single submitter	clinical testing	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).
GeneDx	RCV001310761	SCV005201769	pathogenic	not provided	2024-02-22	criteria provided, single submitter	clinical testing	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)