Nomenclature r. p.

[Dr. Raina Yamamoto]

Dear HGVS support,

 

I have a question about the correct nomenclature of the variant c.299_300del in COL1A1.

 

This variant creates a premature stop codon and is predicted to result in nonsense-mediated mRNA decay (NMD) and a null allele (COL1A1 haploinsufficiency). This variant deletes the two first nucleotides of exon 3 and computer-based splice site predictions indicate that this variant may lead to the use of an alternative splice acceptor site. Usage of this alternative splice acceptor site or skipping of exon 3 is predicted to result in a frameshift, a premature stop codon, NMD and haploinsufficiency. RNA analysis was not performed.

 

We decided to use r.(spl?) (parentheses because it is uncertain) on RNA and p.0? (instead of p.(Glu100Valfs*68)) on protein level.

 

I would like to ask you about the correct nomenclature on RNA and protein level for this variant?

           

Kind regards

 

Raina Yamamoto

 

Dr. rer. medic. Raina Yamamoto

Diplom-Biologe

Leitung Analysebereich Molekulargenetik I

 

Überörtliche Berufsausübungsgemeinschaft - GbR

Medizinisches Versorgungszentrum

Dr. Eberhard & Partner Dortmund

Balkenstr. 12-14

44137 Dortmund, Germany

 

Tel.: +49 231 9572 6666

FAX: +49 231 9572 86667

E-Mail: yama...@labmed.de

Web: www.humangenetik-dortmund.de, www.labmed.de

 

[Johan den Dunnen]

Dear Raina,

please note, you do not mention the reference sequence used. I guess it may be NM_000088.4. I will answer your question assuming you used this reference sequence.

When you want to report the predicted consequences on RNA and protein level it is up to you what to report. When I read "This variant creates a premature stop codon and is predicted to result in nonsense-mediated mRNA decay (NMD) and a null allele (COL1A1 haploinsufficiency)" I get to the description of this variant as NM_000088.:4c.299_300del r.0? p.0?.

"r..0? p.0?" because you indicate the predicted effect is nonsense-mediated mRNA decay and a null allele.

Using "r.(spl?)" seems redundant, it uses both "()" and "?" to indicate uncertainty. r."spl?" is sufficient to indicate you are not sure the variant affects splicing. I would not use "p.(Glu100Valfs*68)" on protein level because you mention you are not sure splicing is affected, and you suspect NMD, making it rather unlikely this protein is actually produced.

Best regards,

Johan den Dunnen
HUGO HGVS Variant Nomenclature Committee (HVNC)

Op vrijdag 11 april 2025 om 13:56:43 UTC+2 schreef Dr. Raina Yamamoto: