Nomenclature


Download pdf file of the current ISTH VWF SSC Guideline on VWF and its activities

The nomenclature for describing VWF and its activities is based on the most recent recommendations of the ISTH Scientific and Standardization Subcommittee on von Willebrand factor, as described by Mazurier and Rodeghiero, Thromb Haemost. 2001; 86: 712.

Recommended abbreviations for von Willebrand factor and its activities:

Attribute
Recommended Abbreviation
Mature protein
VWF
Antigen
VWF:Ag
Ristocetin cofactor activity
VWF:RCo
Collagen binding capacity
VWF:CB
Factor VIII binding capacity
VWF:FVIIIB

Download pdf file of the current ISTH VWF SSC Guideline on VWF gene mutation and polymorphism nomenclature

The nomenclature for describing VWF gene mutations and polymorphisms and the classification of VWD mutations is based on the most recent recommendations of the ISTH Scientific Subcommittee on von Willebrand disease, as described by A.C. Goodeve et al, Thromb Haemost. 2001; 85(5): 929-31.

A series of papers on proposed mutation nomenclature schemes for human genes have been published in Human Mutation produced by the "nomenclature working group", a group of researchers representing interest in mutation detection from different fields of research (1-3). Readers are recommended to refer to these publications, particularly to that of Antonarakis et al (3) for further details of all circumstances where mutation nomenclature is required. As several different numbering schemes have been used for VWF in the past, authors are encouraged to indicate the scheme that is used. At their first mention in a text, mutations may be described in detail, for example alanine substituted by glycine at codon 123; insertion of a guanine following the adenine nucleotide at position 1234. Thereafter, the nomenclature described below should be used.

cDNA sequence

The recommendation for the VWF cDNA is to continue to number from the A of the initiator ATG site as +1. This numbering scheme results in nucleotide numbers 250 nt lower than when numbering VWF from the transcription initiation site (4). The sequence is available under accesion number NM_000552.

Gene DNA sequence

When the entire VWF genomic sequence becomes readily available, genomic DNA nt numbering should start from the initiator ATG as +1, as for the cDNA. However, when numbering, a lower case g for genomic DNA should be used in front of the nt number (eg g.1234), to demonstrate which sequence is referred to. Numbering should be sequential throughout the gene, from 1-178,000 as for the FIX gene (5). The exon or intron number should also be given for orientation. Until the complete VWF gene sequence is readily available, the partial VWF genomic sequence of Mancuso et al (6) may be used when required.

Nucleotide changes

Nucleotide alterations should be referred to as indicated by examples in Table 1. The original and mutated nucleotides are both given following the nucleotide position number, to avoid confusion with amino acid numbering. Various symbols representing the nt substitution can be utilised, such as G->A and G>A. For insertion and deletion mutations, where one or two nt are involved, they should be named. Where >2 nt are involved, only the number involved is required. For deletions or insertions in repetitive sequence eg. AAAAAA, the most 3' nt number is arbitrarily assigned. For intronic changes, where nt close to the intron/exon boundary are numbered, it is simple to use the cDNA numbering with a + or - sign to designate distance into the intron. For alterations deeper into the intron, the full VWF genomic DNA sequence should be used once it is readily available, until then, the sequence of Mancuso et al (6) may be used. When using genomic VWF DNA sequence numbering to describe intronic sequence, the intron number should also be given for orientation. Changes in the upstream untranslated region are numbered from the A of the initiator ATG (+1) as negative numbers.

Nucleotide change
Nomenclature example
Description
Substitution
1234G>A
Guanine substituted by adenine at position 1234 in the VWF cDNA sequence
Substitution
g1234G>A
Guanine substituted by adenine at position 1234 in the complete VWF genomic sequence
Substitution
5/1234G>A
Guanine substituted by adenine at position 1234 in block 5 of the partial VWF genomic sequence of Mancuso et al (7)
Deletion
1234delG
Deletion of guanine from position 1234 of the VWF cDNA sequence
Deletion
1234delN
N nt deleted at position 1234 in the VWF cDNA sequence, N >2 nt
Insertion
1234insGT
Insertion of guanine and thymidine after nt 1234 in the VWF cDNA sequence
Insertion
1234insN
N nt inserted after nt 1234 in the VWF cDNA sequence, N >2nt
Intronic change
1234+1G>T
Substitution of guanine of GT splice donor, 1st position of intron. Nt number 1234 is last nt of preceding exon of the VWF cDNA sequence
Intronic change
1234-2A>G
Substitution of adenine of AG splice acceptor, 2nd last position of intron. Nt 1234 is the first nt of the succeeding exon of the VWF cDNA sequence
Table 1. Recommendations for VWF nucleotide alterations

Amino acid sequence

Numbering should start from the initiator methionine as the +1 position. Separate numbering schemes for mature VWF should be discontinued, so avoiding confusion with amino acid numbering in the propeptide. The use of single letter aa codes will facilitate discrimination from the previous nomenclature, where the three letter amino acid codes were widely used for aa in the mature VWF.

Amino acid alterations

Amino acid alterations should be referred to as indicated by examples in Table 2. The wild type amino acid is given before the codon number and the mutant amino acid following the number. This placement avoids confusion with the nucleotide numbering scheme, where all nucleotides are given following the nucleotide position number. Termination (stop) codons are designated by an X. For insertion or deletion mutations, where one or two aa are involved, they should be named. Where >2 aa are involved, only the number involved is required. For deletions or insertions in repetitive sequence eg. LysLysLys, the most carboxyl (3') aa number is arbitrarily assigned. To facilitate comparison with earlier publications, at the first description in a manuscript of a mutation in mature VWF, the previous nomenclature (for mature VWF, starting from Ser764 of pre-pro VWF) should be given in parenthesis. For this purpose, the three letter aa codes should be utilised.

Amino acid change
Nomenclature example
Description
Missense
R123G
Arginine residue substituted by glycine at position 123 in the pre-pro VWF sequence
Nonsense
R123X
Arginine residue substituted by a stop codon at position 123 in the pre-pro VWF sequence
Insertion
R123insS
Insertion of a serine residue following the arginine residue at position 123 in the pre-pro VWF sequence
Deletion
R123del
Deletion of an arginine residue from position 123 in the pre-pro VWF sequence
Table 2. Recommendations for VWF amino acid alterations

Polymorphisms

Polymorphic alterations should be referred to as indicated by examples in Table 3. Two alleles which co-exist in the population at an arbitrarily designated polymorphic frequency of >1% (7) and have no known deleterious effect on phenotype can be shown at a specified location using a "/" symbol. The first allele shown should be that in the reference sequence available on the VWF electronic database and the second the polymorphic variant. To avoid confusion, for polymorphic aa residues, the aa designations are given before the codon position number, whereas for polymorphic nt, the nt designations are given following the nt position number.

Polymorphic change
Nomenclature example
Description
Single nucleotide polymorphism
1234A/G
Nucleotide 1234 in the VWF cDNA sequence is polymorphic. Two alleles known (adenine and guanine), that in reference sequence shown first
Insertion/deletion polymorphism
1234C/delC
Presence/absence of cytosine at position 1234 in the VWF cDNA sequence is polymorphic
Single amino acid polymorphism
A/G1234
Amino acid residue at position 1234 in the pre-pro VWF sequence is polymorphic. Two alleles known (alanine and glycine), that in reference sequence shown first
Table 3. Recommendations for VWF polymorphism nomenclature

Recommended Abbreviations for VWF and Its Activities

The nomenclature for describing VWF and its activities is based on the most recent recommendations of the ISTH Scientific Subcommittee on von Willebrand disease, as described by C.Mazurier and F.Rodeghiero (8).

Attribute
Recommended abbreviation
Mature protein
VWF
Antigen
VWF:Ag
Ristocetin cofactor activity
VWF:RCo
Collagen binding capacity
VWF:CB
Factor VIII binding capacity
VWF:FVIIIB
Factor VIII coagulant activity
FVIII:C
Table 4. Recommended abbreviations for VWF (and FVIII) and its activities

References

  1. Beaudet AL, Tsui L-C. A suggested nomenclature for designating mutations. Human Mutation 1993; 2: 245-248.
  2. Ad Hoc Committee on Mutation Nomenclature. Update on nomenclature for human gene mutations. Human Mutation 1996; 8: 197-202.
  3. Antonarakis SE, Nomenclature Working Group. Recommendations for a nomenclature system for human gene mutations. Human Mutation 1998; 11: 1-3.
  4. Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994; 71:520-525.
  5. Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K. Nucleotide-sequence of the gene for human factor-IX (antihemophilic factor-B). Biochemistry 1985; 24: 3736-3750.
  6. Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, Alevy YG, Sadler JE. Structure of the gene for human von Willebrand-factor. J Biol Chem 1989; 264: 19514-19527.
  7. Peake I, Winship P. What is a polymorphism. Blood 1991; 78: 251.
  8. Mazurier C, Rodeghiero F. Recommended abbreviations for von Willebrand Factor and its activities. Thromb Haemost 2001; 86: 712.


Download pdf file of the current ISTH SSC VWF Nomenclature Guidelines


This page is maintained by Dan Hampshire
of the Department of Cardiovascular Science at the University of Sheffield