Clarification of closely spaced variants including a frameshift

[Annika Grewal]

Dear HGVS Team,

I'm looking for clarification regarding closely spaced variants in the following case:

I have multiple variants in cis in the GAA gene (NM_000152.5): c.1833_1839del (p.His612ArgfsTer82), c.1846G>T (p.Asp616Tyr), and c.1847_1848insT (p.Val617ArgfsTer19). These have been reported in the Pompe Disease Registry and other sources as a single delins: c.1833_1847delinsACGGGGTAT, p.H612delins.

My question is about interpreting “adjacency” when the most 3′ variant causes a frameshift. Since the frameshift alters the amino acid sequence until the premature termination (after 82 amino acids), does the entire range up to that stop codon count as “affected,” such that any variant within or directly adjacent to this region can be combined into a single delins? Specifically, in this case, because c.1833_1839del causes a frameshift predicted to affect amino acids 612–693, could this be considered adjacent to p.Asp616Tyr and therefore combined into a single delins? Or should these variants remain separate as c.1833_1839del (p.His612fs) and c.1846_1847delinsTAT (p.Asp616fs)?

I’ve reviewed the HGVS website but couldn’t find a specific example addressing this situation. Thank you for your time and consideration!

Best,
Annika

[Johan den Dunnen]

Dear Annika,

in cases like this, to prevent erroneous predictions are made regarding the predicted consequences on protein level, it seems best to report the variant as one delins NM_000152.5:c.1833_1847delinsACGGGGTAT p.(His612_Asp616delinsArgGlyIle).

Still, following HGVS nomenclature, the description NM_000152.5:c.[1833_1839del;1846G>T;1847_1848insT] p.(His612_Asp616delinsArgGlyIle) is also correct.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op woensdag 15 oktober 2025 om 19:27:28 UTC+2 schreef agr...@genomenon.com: