HGVS nomenclature query, two variants in cis

[Joanna Tong]

Hi 

We have seen two variants occur in cis, suggesting they are linked rather than individual mutations. Please see the figure attached. Although HGVS suggests separate descriptions for variants with intervening nucleotides, we believe a single delins is more biologically sound in this context. We would appreciate your guidance on the correct way to report this: should we strictly follow the HGVS 'individual' rule (Option 1), or is the 'delins' approach acceptable given the physical linkage (Option 2)? Or to report DNA and RNA changes individually but provide a single, unified protein change (Option 3).

 

Option 1 To describe as two individual variants: (HGVS recommendation)

9:5070033GAAATGA>G NM_004972.4:c.1624_1629del

NP_004963.1:p.(Asn542_Glu543del)

 

9:5070043T>C NM_004972.4:c.1632T>C
NP_004963.1:p.(Asp544=)

 

Option 2 To describe as one Delins

9:5070035:AATGAAGAT>GAC NM_004972.4:c.1624_1632delinsGAC NP_004963.1:p.(Asn542_Glu543del)

 

Option 3 Combine option 1 and 2    

[9:5070033GAAATGA>G; 9:5070043T>C] NM_004972.4:[1624_1629del;1632T>C] NP_004963.1:p.(Asn542_Glu543del)

 

Thanks and regards

Joanna

[Johan den Dunnen]

Dear Joanna,

first, please note that a description like "[9:5070033GAAATGA>G; 9:5070043T>C does not follow HGVS nomenclature. Correct is NC_000009.12:g.[5070035_5070040del;5070043T>C].

Following HGVS nomenclature, the variant should be described as NC_000009.12:g.[5070035_5070040del;5070043T>C] NM_004972.4:[c.1624_1629del;1632T>C] p.(Asn542_Glu543del).

However, an upcoming proposal will contain the remark: "Data providers may report adjacent variants independently and may merge nearby (non-adjacent) variants if they believe that those forms are more suitable for their data". This would allow the description NC_000009.12:g.5070035_5070043delinsGAC NM_004972.4:c.1624_1632delinsGAC p.(Asn542_Glu543del).

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op dinsdag 30 december 2025 om 14:56:59 UTC+1 schreef joanna...@gmail.com:

[Joanna Tong]

Hi Johan,

Thank you very much for your reply! really appreciated!

Wish you a good start of 2026!

Joanna