Rejected proposal SVD WG010

[Maida Ljubijankic]

Dear HGVS,

I have several questions regarding the proposal at: https://hgvs-nomenclature.org/stable/consultation/SVD-WG010/, which was recently rejected.

First, I would like to clarify what exactly was rejected in this proposal (specifically on the linked page). Was the entire content up to the “Background” actually rejected? And if I can have more details on why specifically this proposal was rejected?

My second question concerns delins at the protein level. According to the page at https://hgvs-nomenclature.org/stable/recommendations/protein/delins/, it is still stated that "changes involving two or more consecutive amino acids are described as a deletion/insertion variant (delins)." I would like to confirm whether this guidance still applies? Specifically, can we still describe delins at the protein level even if, at the cDNA level, the changes might be separated by one or more base pairs?

Lastly, here are some examples I’m wondering how to describe in light of the rejection of the proposal:

1. AGL1 gene: NM_019109.5:c.740G>T; c.740+5G>A. I assume that now these should be described individually and not as c.740_740+5delinsTGTAGA? Of note, delins variant is described as delins in several databases (old submissions).
2. Another example is related to the first part of this proposal that I was wondering if got rejected. Gene BMPER: NM_001365308.1:c.496T>A; 501_502delGT. Specifically, the part related to 3' rule where it is stated that: "...for the purposes of evaluating adjacency we can shift in the opposite direction to determine the point of closest distance". Does this mean that we cannot shift to the left to determine the point of closest distance and describe the variant as c.496_498delinsA as suggested by Mutalyzer and some other databases as well?

Thank you very much!

Kind regards,

Maida Ljubijankic

[Johan den Dunnen]

Dear Maida,

indeed, proposal SVD-WG010 has been rejected which means that the recommendations stay unchanged, i.e.;

- substitutions involving two or more consecutive nucleotides are described as deletion/insertion (delins) variants.
- two variants separated by one or more nucleotides should be described individually and not as a "delins" of the sequence affected. Exception: two variants separated by one nucleotide, together affecting one amino acid, should be described as a "delins".

The proposal was rejected because there were too many objections. At first sight it might be the proposal simplified HGVS nomenclature but, as several have pointed out, not all cases can be covered unequivocally by the proposal. Accepting the proposal would thus give conflicts.

Regarding your other questions;

- does the recommendation "changes involving two or more consecutive amino acids are described as a deletion/insertion variant (delins)." still apply: YES.

- the description NM_019109.5:c.[740G>T;740+5G>A] is correct, c.740_740+5delinsTGTAGA does not follow current HGVS recommendations.

- the description NM_001365308.1:c.496_498delinsA is following HGVS nomenclature, in a case like this it is allowed to shift in the opposite direction to determine the point of closest distance

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op donderdag 8 mei 2025 om 10:54:21 UTC+2 schreef mljubi...@genomenon.com: