a sequence change where, compared to a reference sequence, one amino acid is replaced by one other amino acid.
Format: “prefix”“amino_acid”“position”“new_amino_acid”, e.g. p.(Arg54Ser)
“prefix” = reference sequence used = p. “amino_acid” = reference amino acid = Arg “position” = position amino acid subtituted = 54 “new_amino_acid” = new amino acid = Ser
prefix reference sequence accepted is “p.” (protein).
predicted consequences, i.e. without experimental evidence (no RNA or protein sequence analysed), should be given in parentheses, e.g. p.(Arg727Ser).
changes involving two or more consecutive amino acids are described as deletion/insertions (indels) (see Deletion/insertion (indel)). NOTE: when either of two directly flanking substitution variants is known as a regularly occurring variant, the variants are described individually and not as a “delins”.
a nonsense variant, a variant changing an amino acid to a translation termination (stop) codon, is described as a substitution. NOTE: a nonsense variant is not described as a Deletion of the C-terminal end of the protein (e.g. p.Trp26_Arg1623del)
amino acids that have been tested and found not changed are described as p.Cys123= (see SVD-WG001 (no change)). NOTE: the underlying DNA change must be given in addition and in this case is either c.456C>T or c.456C= NOTE: such changes are silent protein changes
the description p.Arg76_Cys77delinsSerTrp is preferred over p.[Arg76Ser;Cys77Trp]. NOTE: by definition this change can not be described as a substitution (like p.Arg76_Cys77SerTrp)
it is not correct to describe “polymorphisms” as p.76Ser/Arg (see Discussions).
amino acid Trp24 is changed to a Cys
amino acid Trp24is predicted to change to a Cys (no experimental proof, e.g. based on DNA level data)
amino acid Trp24 is changed to a stop codon (Ter, *) NOTE: this change is not described as a deletion of the C-terminal end of the protein (i.e. p.Trp24_Met36853del)
silent (no change)
amino acid Cys188 is not changed (DNA level change ..TGC.. to ..TGT..)
NOTE: the description p.= means the entire protein coding region was analysed and no variant was found that changes (or is predicted to change) the protein sequence.
translation initiation codon
description depends on the consequences of the change on the translation product (protein);
as a consequence of a variant no protein is produced
the consequence of a variant at the protein level are not known (can not be predicted)
a variant causes the inactivation of the normal and activation of a downstream translation initiation site (Met) resulting in deletion of the first 123 amino acids (Met-1 to Val-123) of the protein. NOTE: the 3’ rule applies.
amino acid Gly56 is changed to an Ala, Ser or Cys (see Uncertain)
a mosaic case where at amino acid position 24 besides the normal amino acid (a Trp, described as “=”) also protein is found containing a Cys (Trp24Cys)
NOTE: for the predicted consequences of a variant the description is LRG_199t1:p.(Trp24=/Cys)
Are polymorphisms described like p.2366Gln/Lys?
No, all substitutions are described as NP_003997.1:p.Gln2366Lys. In the past, the format p.2366Gln/Lys (p.2366Q/K) has been used to describe "polymorphic" sequence variants. Note that a description should be neutral, simply describe the change, and not include any other information like predicted or known functional consequences.
Can I describe a TrpVal to CysArg variant as a amino acid substitution (p.TrpVal24CysArg)?
No, this is not allowed. By definition a substitution changes one amino acid into one other amino acid. The change TrpVal to CysArg should be described as NP_003997.1:p.Trp24_Val25delinsCysArg, i.e. a deletion/insertion (indel) (see Deletion-Insertion).
How should you describe an amino acid substitution to any other amino acid?
HGVS uses IUPAC symbols (see Standards). The symbol for 'any' amino acid is 'X'/'Xaa'. Since 'X' has been used to indicate a translation stop codon (nonsense variant) we suggest to use 'Xaa' three-letter amino acid code only (e.g. p.Arg782Xaa).