Defining reference alleles as "normal" or "normal function" alleles

[David W. Hein]

My question relates specifically to arylamine N-acetytransferase (NAT2).  Historically, NAT2 alleles have been identified as rapid acetylator  or slow acetylator depending upon expression of the NAT2 protein and subsequent catalytic activity.  Rapid acetylator alleles are associated with drug toxicity when N-acetylation is an activation pathway.  Slow acetylator alleles are  associated with drug toxicity when N-acetylation is a deactivation pathway.  The opposite is true for drug efficacy.    A paper describing this is attached. 

Frequency of rapid acetylator and slow acetylator alleles are high but vary considerably with ethnic origin.  I do not think it would be appropriate to identify rapid acetylator or slow acetylator alleles as "normal" or "normal function".  Rather, I feel "high" or "low" function is more appropriate.  The argument I have heard is that "normal function" is frequently used and should be appropriate for NAT2 as it is for other genes.  I think "normal" is only appropriate when it refers to an allele associated with a disease rather than an allele that modifies metabolism of drugs and xenobiotics.

I would welcome comments and advice on this.  Thank you in advance.

[Johan den Dunnen]

Dear David,

HGVS nomenclature is a standard to describe variants in DNA, RNA and protein sequences. All variants are described in relation to a reference sequece. As such, the reference is the "standard". The issue you raise is beyond the HGVS nomenclature standard, we do not use terms like "normal", "high", "low", etc. We only use "variant".

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op vrijdag 7 februari 2025 om 16:08:04 UTC+1 schreef dwhe...@gmail.com: