a variant in the translation initiation codon causes the 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.
upstream - p.Met1_Leu2insArgSerThrVal (insertion)
a variant in the translation initiation codon (Met1) changes it to a Valine (Val) and activates an upstream translation initiation site at position -4, replacing amino acid Met1 with MetArgSerThrVal. Applying the 3’ rule the variant is described as an insertion.
NOTE: this variant is not described as an extension
new - p.Met1ext-5 (extension)
a variant in the 5’ UTR activates a new in-frame upstream translation initiation site starting with amino acid Met-5 (see Extension)
the predicted consequence of variant NM_004006.2c.2622G>C is a silent change (p.(Lys874=)). Since it affects the last nucleotide of the exon it can not be excluded the variant affects splicing, having unknown consequences.
NOTE: when others have reported the same variant, and were able to analyse RNA, you could consider to give the consequences they observed as the predicted consequences for the variant, e.g. r.[(2603_2622del,2622g>c)] p.[(Ser868Argfs*2,Ser868=)]
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: irrespective of the frequency in which each amino acid was found, the reference is always described first
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).