a series of variants in a protein encoded by one chromosome.
Format (one allele): “prefix”[“variant1”;”variant2”], e.g. p.[(Ser73Arg;Asn103del)]
“prefix” = reference sequence used = p. [ = opening symbol for allele = [ “variant1” = description first variant = Ser73Arg ; = separator symbol two changes = ; “variant2” = description second variant = Asn103del ] = closing symbol for allele = ]
Format (two alleles): “prefix”[“variant”];[“variant”], e.g. p.[(Ser73Arg)];[(Asn103del)]
“prefix” = reference sequence used = p. [ = opening symbol for allele-1 = [ “variant” = description variant = Ser73Arg ];[ = closing symbol for allele-1, separator symbol two alleles, opening symbol for allele-2 = ];[ “variant” = description variant = Asn103del ] = closing symbol for allele-2 = ]
all variants should be described at the DNA level, descriptions at the RNA and/or protein level may be given in addition
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 inside the square brackets, e.g. p.[(Arg727Ser);(Cys1334Trp)]
when two variants are identified in a protein that derive from one chromosome (in cis) this should be described as “p.[variant1;variant2]”
when two variants are identified in proteins that derive from different chromosomes (in trans) this should be described as “p.[variant1];[variant2]”
when two variants are identified in a protein, but when it is not known whether these derive from one chromosome (in cis) or from different chromosomes (in trans), this should be described as “variant(;)variant2”, i.e. without using “[ ]”
NOTE: it is recommended to determine whether the changes are in the same protein or not
when two variants are identified in two different proteins that derive from one variant at the DNA level (giving two different transcripts) the variants are separated using a “,”; p.[variant1,variant2]”
a protein allele contains two different variants, p.Ser68Arg and p.Asn594del (the variants are found in cis)
a protein allele contains two different predicted variants, p.(Ser68Arg) and p.(Asn594del) (the variants are found in cis)
NOTE: the parentheses are placed inside of the allele brackets, the description p.([Ser68Arg;Asn594del]) is not correct
variants on different alleles
two protein alleles contain the same variant, p.Ser68Arg (the variants are found in trans, e.g. in a recessive disease)
two protein alleles contain the same variant with a predicted consequence p.(Ser68Arg)
NOTE: the parentheses are placed inside of the allele brackets, the description p.([Ser68Arg];[Ser68Arg]) is not correct
a possible homozygous case where one protein allele contains predicted variant p.(Ser68Arg), but where it can not be excluded the other allele is deleted
two protein alleles each contain a different variant, p.Ser68Arg and p.Asn594del (compound heterozygote, e.g. in a recessive disease, the variants are found in trans)
one protein allele contains a variant, with predicted consequence p.(Ser68Arg), while a variant for the other protein allele is expected but not yet identified (p.(?)) (e.g. in individuals affected by a recessive disease).
one protein allele contains a variant, p.Ser68Arg, the other allele contains at this position the reference sequence, Ser68= (is wild-type).
NOTE: for other variant types the format is p.[Ser68del];[Ser68=], p.[Ser68_Arg70dup];[Ser68_Arg70=], p.[Ser68_Ala74insSerGln];[Ser68_Ala74=], etc. (based on Proposal SVD-WG001).
NOTE: using p.[=] would mean the entire NP_003997.1 protein reference sequence was tested and found not changed
two predicted protein variants are found, p.(Ser68Arg) and p.(Asn594del), but it is not known whether they are on the same or on different alleles (chromosomes).
NOTE: when it is not known on which allele a variant is, allele brackets are not used
for the variants NM_004006.3:c.472A>G and c.473A>T it is not known whether they are on the same or on different alleles (chromosomes). The predicted consequence when the variants are on different alleles is p.(Asn158Asp)(;)(Asn158Ile), when the variants are on the same allele (i.e. c.472_473delinsGT) the predicted consequence is p.(Asn158Val). To discriminate between the two possibilities square brackets need to be used.
one allele encoding two proteins
two different proteins, p.Lys31Asn and p.Val25_Lys31del, derive from a variant on one allele (c.93G>T at the DNA level with r.[83g>u,73_93del] at the RNA level).
Was originally the recommendation to use the format [p.Ser73Arg+p.Asn103del]?
Indeed, originally den Dunnen and Antonarakis, 2000 the suggestion was to describe two changes in a protein encoded by one chromosome as [p.Ser73Arg+p.Asn103del], i.e. using a "+"-character to separate the two changes, while an earlier publication suggested to use a ";" ([p.Ser73Arg;p.Asn103del] (Antonarakis and the Nomenclature Working Group, 1998). To prevent confusion with older publications, to improve overall consistency and to keep descriptions as short as possible, the 2000 proposal was retracted. The recommended format is p.[Ser73Arg;Asn103del].
Can I describe the predicted protein consequences of two variants on the same allele as p.([Phe233Leu;Cys690Trp])?
No, this should be described as p.[(Phe233Leu;Cys690Trp)], i.e. with the parentheses inside the square brackets of the allele and around each variant. This format is used for overall consistency; with the parentheses inside the square brackets variants can be described as p.[Phe233Leu;(Cys690Trp)] which would not be possible when they were allowed outside of the square brackets.
In recessive diseases, is it important I show which variants were found in which combination?
When in one individual you find more then one variant it is essential that you clearly indicate which variant(s) were found and in the protein from which allele(s);
disease severity will depend on the combination of variants found,
in recessive disease, when two variants are in the protein from one allele an individual is a carrier or you might not have found the variant in the protein from the 2nd allele.
I find the notation p.[Ser73Arg] without describing the second protein allele misleading; not enough researchers know this refers to only one of the two alleles present. Would using p.[Ser73Arg]; be OK?
No, the recommended description is p.[Ser73Arg];[Ser73=], i.e. p.Ser73= for "no change" on the second protein allele.
How should I describe the variants detected in males and females for a protein encoded by the X-chromosome?
In females the description is straightforward, like p.[Ser86Arg];[Ser86=]. In males there is no second allele (X-chromosome) which can be described as p.[Ser86Arg];, i.e. using "p.0" to indicate the absence of a protein from the second X-chromosome. A description like p.[Ser86Arg]; is also possible for a female but, since variant descriptions on protein level can only be given in addition to a description on DNA level, it will be linked to either the description of a deletion on DNA level or the absence of RNA (r.0), e.g. caused by non-random X-inactivation.