Two consecutive substitutions in different codons

[Yang Wang]

Hello, I want to get your opinion on for clinical reporting when two consecutive nucleotide substitutions are in different codons and one of them is a benign and the other is a pathogenic variant. Would you report as delins as recommended in the current HGVS or report only the pathogenic substitution?  Many thanks!

[Johan den Dunnen]

Dear Y Wang,

the answer to your question can be found on the HGVS nomenclature page https://hgvs-nomenclature.org/stable/consultation/SVD-WG010/. Proposal SVD-WG010 has not yet been officially accepted but any modifications will not affect the answer to your question.

So, regarding your question, the recommendation is to describe the variants together, as a "delins". However, please also note the remark starting with "Data providers may report...".

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)
http://www.HGVS.org/varnomen

Op woensdag 11 september 2024 om 21:31:43 UTC+2 schreef yw...@natera.com:

[John Lattier]

I also want to know the answer to this. There are 

• Rules about combining neighboring variants on the same codon ✅
• Rules about combining variants separated by 1 intervening nucleotide but impacting the same codon ✅
• Rules that loosely state that neighboring nucleotides should be combined as delins but without respect to if it's impacting a single codon or two neighboring codons ❓
  • No rules that explicitly state how to treat a pair of variant like this:
  • DYSF [NM_003494.4] c.1455C>T (p.I485M)
  • DYSF [NM_003494.4] c.1456T>A (p.S486T) in cis
  • ? Combine to c.1455_1456delinsGA (p.I485_S486delinsMT)? 
  • ? Or keep as two separate missense in cis?

[Johan den Dunnen]

Dear John,

following HGVS nomenclature the variant should be described as NC_000002.12:g.71539214_71539215delinsTA. The description NM_003494.3:c.1455_1456delinsTA p.(Ser486Thr) may be added.

This follows the rule "substitutions involving two or more consecutive nucleotides are described as deletion/insertion (delins) variants" (see https://hgvs-nomenclature.org/stable/recommendations/DNA/substitution/).

Please note that "DYSF [NM_003494.4] c.1455C>T (p.I485M)" is not a description following HGVS nomenclature. It is mandatory to describe a variant on genomic level (NC_000002.12:g.71539214C>T), correct is NM_003494.4:c.1455C>T (HGVS does not use gene symbols in variant descriptions) and the predicted consequence of the variant is not p.(Ile485Met) but p.(=).

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op dinsdag 30 december 2025 om 14:57:26 UTC+1 schreef John Lattier:

[John Lattier]

Thanks, I had meant c.1455C>G (p.I485M)