Protein Recommendations

Substitution Variant


Definitions

Substitution
a sequence change where, compared to a reference sequence, one nucleotide is replaced by one other nucleotide.

Description

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


Note

  • prefix reference sequence accepted is “p.” (protein).
  • predicted consequences, i.e. without experimental evidence (no RNA or protein 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)).
  • 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).

Examples

  • missense
    • p.Trp26Cys
      amino acid Trp26 is changed to a Cys
    • p.(Trp26Cys)
      amino acid Trp26 is predicted to change to a Cys (no experimental proof, e.g. based on DNA level data)
  • nonsense
    • p.Trp26Ter (p.Trp26*)
      amino acid Trp26 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.Trp26_Arg1623del)
  • silent
    • p.Cys123=
      amino acid Cys123 is not changed (DNA level change ..TGC.. to ..TGT..)
  • translation initiation codon
    description depends on the consequences of the change on the translation product (protein);
    • p.0
      as a consequence of a variant no protein is produced
    • p.? (p.Met1?)
      the consequence of a variant at the protein level are not known (can not be predicted)
  • new translation initiation site
    • upstream - see Extension
    • downstream - p.Phe2_Met46del
      a variant causes the inactivation of the normal and activation of a downstream translation initiation site (Met) resulting in deletion of the first 45 amino acids (Met-1 to Lys-45) of the protein.
      NOTE: the 3’ rule applies.
  • translation termination codon (stop codon, no-stop change)
    see Extension
  • p.(Gly19Ala^Ser^Cys)
    amino acid Gly19 is changed to an Ala, Ser or Cys (see Uncertain)

Q&A

Are polymorphisms described like p.45Arg/Ser?

No, all substitutions are described as p.Arg45Ser. In the past, the format p.45Arg/Ser (p.45R/S) 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 TrpSer to CysArg variant as a amino acid substitution (p.TrpSer23CysArg)?

No, this is not allowed. By definition a substitution changes one amino acid into one other amino acid. The change TrpSer to CysArg should be described as p.Trp23_Ser24delinsCysArg, i.e. a deletion/insertion (indel) (see Deletion-Insertion).