Submissions for variant NM_000132.4(F8):c.6744G>T (p.Trp2248Cys)

dbSNP: rs137852469

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV000011040	SCV004363655	pathogenic	Hereditary factor VIII deficiency disease	2024-02-02	reviewed by expert panel	curation	The NM_000132.3(F8):c.6744G>T (p.Trp2248Cys) is reported in at least 19 patients with mild, moderate or severe hemophilia A in the literature reviewed (PMID: 17222201, 18691168, 15921397, 1301932, 17610560). There are several additional probands with the variant reported in the EAHAD database, recorded from the literature and unpublished sources. There are also individuals reported with a history of inhibitor development to factor VIII replacement therapy (EAHAD/CDC Champs Databases). The variant is absent from gnomAD v2.1.1 and v3 meeting PM2_Supporting. This missense variant has a REVEL score of 0.925 (>0.6), meeting criteria for PP3. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8/F9: PS4_Very Strong, PP3, PM2_Supporting.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851849	SCV000899866	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003114185	SCV003800119	pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	The F8 c.6744G>T; p.Trp2248Cys variant (rs137852469), also known as W2229C in traditional nomenclature, is reported in the literature in multiple individuals affected with mild to severe hemophilia A (Diamond 1992, Markoff 2009, Naylor 1991, see link to FVIII database). This variant is also reported in ClinVar (Variation ID: 10327). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The tryptophan at codon 2248 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.925). Additionally, other variants at this codon (c.6742T>A, p.Trp2248Arg; c.6742T>C, p.Trp2248Arg; c.6743G>C p.Trp2248Ser) have been reported in individuals with mild to severe hemophilia A (Markoff 2009, Santacroce 2008, Shinozawa 2021, Yenchitsomanus 2003). Based on available information, this variant is considered to be pathogenic. References: Link to FVIII database: https://f8-db.eahad.org/index.php Diamond C et al. Amino acid substitutions in conserved domains of factor VIII and related proteins: study of patients with mild and moderately severe hemophilia A. Hum Mutat. 1992;1(3):248-57. PMID: 1301932. 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. PMID: 19473423. Naylor JA et al. Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene. Lancet. 1991 Mar 16;337(8742):635-9. PMID: 1671991. Santacroce R et al. Identification of 217 unreported mutations in the F8 gene in a group of 1,410 unselected Italian patients with hemophilia A. J Hum Genet. 2008;53(3):275-284. PMID: 18217193. Shinozawa K et al. Spectrum of F8 Genotype and Genetic Impact on Inhibitor Development in Patients with Hemophilia A from Multicenter Cohort Studies (J-HIS) in Japan. Thromb Haemost. 2021 May;121(5):603-615. PMID: 33254277. Yenchitsomanus P et al. Genotype and phenotype of haemophilia A in Thai patients. Haemophilia. 2003 Mar;9(2):179-86. PMID: 12614369.
OMIM	RCV000011040	SCV000031267	pathogenic	Hereditary factor VIII deficiency disease	1992-01-01	no assertion criteria provided	literature only