HGVS protein nomenclature

[Sock Hoai Chan]

Dear HVGS support,

I would like to seek clarification regarding placement of parenthesis for the protein nomenclature. 

I had described my variant as this:

LDLR, NM_000527.5:c.326G>T, NP_000518.1:p.Cys109Phe

My understanding of the HGVS recommendation for protein nomenclature is that when the consequence is predicted, then the parentheses are placed as NP_000518.1:p.(Cys109Phe).

But if there is RNA/protein data to experimentally demonstrate/support the functional consequence, then parentheses are not required and can be written as NP_000518.1:p.Cys109Phe or written as (p.Cys109Phe). 

For this variant, it has been experimentally described in the literature to affect LDLR function (PMID:35568682). Does this mean I can describe my variant as NP_000518.1:p.Cys109Phe ?

I subscribed to an EQA scheme that deducted points in my submission for not describing the variant as p.(Cys109Phe) according HGVS guidelines; so I am confused whether my interpretation of the guidelines was wrong.

Thank you very much for your assistance.

Sincerely,

Sock Hoai

[Johan den Dunnen]

Dear Sock,

the variant you mention should be described as NC_000019.10:g.11105232G>T NM_000527.5:c.326G>T p.(Cys109Phe).

Note the variant should be described at genomic level as well. Since I assume you want to report the results of the analysis YOU have performed, the predicted consequences at protein level should be described as p.(Cys109Phe).

Of course you can mention others have performed an assay to test the functional consequences of variant NP_000518.1:p.Cys109Phe. Note however (maybe I missed something in my quick check), the study you mention used expression of a cDNA-construct, so did not check what the possible consequences of the variant at the RNA level are (it might e.g. affect splicing making the cDNA construct data unreliable/incomplete). 

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op maandag 22 juni 2026 om 18:22:10 UTC+2 schreef sock...@gmail.com:

[Sock Hoai Chan]

Dear Johan,

Thank you very much for your explanation.

In the paper by Graca et al (PMID:35568682), it is mentioned that 'For every variant, the presence of the correct variant and integrity of the region was confirmed by direct Sanger sequencing.' with respect to the cDNA construct generated. May I check that this, together with their presented Western blot and FACS quantification data showing this variant has ~50% reduction in LDLR activity, do not meet the experimental evidence indicated in the HGVS guidelines as sufficient to drop the parentheses?

May I clarify what constitutes experimental evidence for deciding placement of the parentheses? (RNA sequencing, what sort of experimental evidence is acceptable for analyzing protein sequence?)

In that case, may I also check, would it be wrong if I describe a variant with parentheses, e.g. p.(Cys109Phe), when there are papers describing functional consequence of the variant (but detailed confirmation such as RNA analysis is not always explicitly reported)? For clinical reporting, it then would not be wrong if I always use p.(Cys109Phe), is that right?

I appreciate your time for addressing my questions.

Thank you very much.

Sincerely,

Sock Hoai