Request for Assistance with Variant Nomenclature – COL1A2 Deletion

[Shalini S. Nayak]

Dear All,

We have identified a 3 bp deletion at chr7:94409817_94409819 (TTG) in the COL1A2 gene. The patient presents with a severe osteogenesis imperfecta phenotype (type III). Typically, haploinsufficiency leads to a milder presentation compared to a dominant-negative mechanism.

Visualization using Integrative Genomics Viewer (IGV) of the exome data indicates a deletion of the first TTG. Based on the IGV data, the variant would be described as:

NM_000089.4:c.1031_1033del p.(Val345del)

However, applying the 3' rule, the deletion could be interpreted as a splice donor variant:

NM_000089.4:c.1035_1035+2del

We would appreciate your guidance on which nomenclature is most appropriate in this case. Should we adhere to the interpretation based on IGV visualization, or apply the 3' rule strictly?

Thank you in advance for your help.

Best regards

Shalini

[Reece Hart]

Dear Shalini-

Sequencing cannot identify which bases are deleted in repeat regions. When you view the deletion in IGV, you are viewing one possible location that is chosen by convention for VCF; that convention happens to be exactly the opposite convention to the one chosen by HGVS. Neither is correct in the sense that both are overly precise about where a variant occurs.

Instead, I recommend that you view deletions and insertions in repeat regions as occurring *somewhere* between the left- and right-shuffled extrema (but, again, sequencing can't tell you where).

https://pmc.ncbi.nlm.nih.gov/articles/PMC8929418/#fig3 might help. 

-Reece

--
You received this message because you are subscribed to the Google Groups "HGVS Nomenclature" group.
To unsubscribe from this group and stop receiving emails from it, send an email to hgvs-nomenclat...@googlegroups.com.
To view this discussion visit https://groups.google.com/d/msgid/hgvs-nomenclature/05ac5053-1bfb-446b-be30-aaf02ce1d5c6n%40googlegroups.com.

[Johan den Dunnen]

Dear Shalini,

as Reece indicated, HGVS nomenclature covers the standardized description of variants, NOTthe interpretation of the consequences of variants. Following HGVS nomenclature recommendations, the variant should be described as NC_000007.14:g.94409821_94409823del NM_000089.4:c.1035_1035+2del.

As you indicate, since the deletion variant is in a region (TTGTTgt) where sequences can be shifted 5' or 3' with quite different possible consequences it will be difficult to predict the consequences at the RNA level, i.e. affecting splicing or not. For this further analysis will be required.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)
 

Op zaterdag 4 oktober 2025 om 18:12:11 UTC+2 schreef re...@harts.net: