ClinVar Miner

Submissions for variant NM_000132.3(F8):c.1569G>T (p.Leu523=) (rs782733685)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506453 SCV000603518 pathogenic Hereditary factor VIII deficiency disease 2018-08-21 criteria provided, single submitter clinical testing The F8 c.1569G>T; p.Leu523Leu variant (rs782733685), also known as Leu504Leu, is described in the medical literature in several individuals with mild hemophilia (Bogdanova 2007, Diamond 1992, El-Maarri 2005, Green 2008, Tavassoli 1998, Tuddenham 1991, Vidal 2001). This variant is reported in ClinVar (Variation ID: 439678), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Functional studies show that this variant results in altered mRNA splicing that deletes 36 nucleotides from exon 11, leaving the rest of the protein in frame (El-Maarri 2005, Tavassoli 1998). Based on available information, the p.Leu523Leu variant is considered to be pathogenic for mild hemophilia A. References: Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. 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. El-Maarri O et al. Analysis of mRNA in hemophilia A patients with undetectable mutations reveals normal splicing in the factor VIII gene. J Thromb Haemost. 2005 Feb;3(2):332-9. Green PM et al. Haemophilia A mutations in the UK: results of screening one-third of the population. Br J Haematol. 2008 Oct;143(1):115-28. Tavassoli K et al. Identification of four novel mutations in the factor VIII gene: three missense mutations (E1875G, G2088S, I2185T) and a 2-bp deletion (1780delTC). Hum Mutat. 1998 Suppl 1:S260-2. Tuddenham EG et al. Haemophilia A: database of nucleotide substitutions, deletions, insertions and rearrangements of the factor VIII gene. Nucleic Acids Res. 1991 19(18):4821-33. Vidal F et al. Rapid hemophilia A molecular diagnosis by a simple DNA sequencing procedure: identification of 14 novel mutations. Thromb Haemost. 2001 Apr;85(4):580-3.

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