Factor VIII Gene (F8) Variant Database  

The reference sequence used for FVIII protein is NP_000123.1 and its corresponding stable Locus Reference Genomic DNA sequence (LRG) is LRG_555. Codons and amino-acids are numbered on this site in two ways. In HGVS numbering, codons are numbered with codon +1 coding for the first residue (Met) of the 19-residue signal peptide (this is -19 in Legacy numbering). In Legacy numbering, codon +1 refers to that coding for the first amino-acid of the mature FVIII protein (in HGVS numbering, this is codon +20). HGVS numbering is recommended, however Legacy numbering is extensively used in FVIII publications, particularly before the year 2000.

Variants causing haemophilia A are classified by factor VIII clotting activity level into the following groups: severe (≤1%), moderate (1-5%) and mild >5%. Where a laboratory value does not correlate with the severity given in a particular report we have attempted to clarify the discrepancy with the original authors. If the discrepancy remains, the clinical severity of the phenotype as reported by the authors has been used. Note that the reported level may reflect a trough level rather than the true baseline in patients on prophylaxis. This may explain why a variant that should result in a null allele is associated with detectable factor VIII activity or antigen. For variants causing mild haemophilia A we have attempted to indicate whether the deleterious effect of the mutation is predominantly quantitative (reduced levels of a normally functioning protein) or qualitative (dysfunctional protein which may or may not also be associated with a reduction in protein level). This is indicated in results tables under the "Type" heading using the conventions used for other coagulation proteins so that Type I refers to quantitative defects with an activity:antigen ratio >0.7 and Type II are qualitative defects with a ratio ≤ 0.7. These categories broadly correspond respectively to the terms CRM (cross-reacting material) negative and positive sometimes found in older publications.

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This work was supported through a medical educational grant from Pfizer UK Ltd.

We thank the Special Trustees of the Royal Free Hospital and the Katharine Dormandy Trust for Haemophilia and Related Disorders for their support.

We thank the European Association for Haemophilia and Allied Disorders (EAHAD) for supporting our work.

We thank the Medical Research Council for their supporting the Database from 1987 to 2010.

The following people worked on this project:

• Pavithra M Rallapalli, formerly of UCL, London
• Geoffrey Kemball-Cook, The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London
• Edward G. Tuddenham, The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London
• Keith Gomez, The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free Hospital, London
• Stephen J Perkins, UCL, London

Recent publication on the EAHAD Coagulation Factor Databases:
The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers. McVey JH, Rallapalli PM, Kemball-Cook G, Hampshire DJ, Giansily-Blaizot M, Gomez K, Perkins SJ, Ludlam CA.
Access here: Haemophilia. 2020 Mar;26(2):306-313. doi: 10.1111/hae.13947.