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. Author manuscript; available in PMC: 2021 Mar 16.
Published in final edited form as: Hum Mutat. 2020 Dec 10;42(1):3–7. doi: 10.1002/humu.24144

Verifying nomenclature of DNA variants in submitted manuscripts: Guidance for journals

Jan Higgins 1, Raymond Dalgleish 2, Johan T den Dunnen 3, Greg Barsh 4,5, Peter J Freeman 6, David N Cooper 7, Sara Cullinan 8, Kay E Davies 9, Huw Dorkins 10,11, Li Gong 12, Issei Imoto 13, Teri E Klein 12, Bruce Korf 14, Adya Misra 15,16, Mark H Paalman 17, Sarah Ratzel 8, Juergen K V Reichardt 18, Heidi L Rehm 19,20,21, Katsushi Tokunaga 12,22, Karen E Weck 23,24, Garry R Cutting 25
PMCID: PMC7961887  NIHMSID: NIHMS1678261  PMID: 33252176

Abstract

Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential. To address this issue, the Human Variome Project convened a committee to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. After a pilot study of two journals, the committee agreed that requiring authors to verify that variants complied with Human Genome Variation Society nomenclature is a reasonable step toward standardizing the worldwide inventory of human variation.

Keywords: ClinVar, DNA variants, Human Genome Variation Society, Leiden Open Variation Database

1 |. INTRODUCTION

Documenting variation in our genomes is important for research and clinical care. Accuracy in the description of DNA variants is therefore essential (Tack et al., 2016; Yen et al., 2017). To address this issue, the Human Variome Project (HVP; https://www.humanvariomeproject.org/) under the auspices of Global Variome (GV) convened a committee (HVP/GV Reporting of Sequence Variants Working Group) to evaluate the feasibility of requiring authors to verify that all variants submitted for publication complied with a widely accepted standard for description. Members of the committee represented expertise in journal publication, variant description, and data sharing. Following a series of monthly committee discussions and consultations with external experts over a 2-year period, a consensus was reached that all published variants should conform to criteria developed by the Human Genome Variation Society (HGVS; https://varnomen.hgvs.org/). Furthermore, committee members agreed that authors were responsible for the accuracy of variant description and should, at a minimum, be required to confirm in writing that all variants reported in their manuscripts conformed to HGVS criteria. In addition, the committee recommended that editors request evidence of verification in the form of output files from online publicly available software tools or records documenting submission to online databases that verified nomenclature (e.g. ClinVar [https://www.ncbi.nlm.nih.gov/clinvar/, Landrum et al., 2020]; Leiden Open Variation Database [LOVD; https://www.lovd.nl/, Fokkema et al., 2011]). Provision of such evidence would assist authors and editors should database curators or others question variant description, as well as identify variants that cannot be defined according to HGVS criteria.

2 |. RECOMMENDED GUIDELINES

  1. The variant description must adhere to current recommendations of the HGVS (den Dunnen et al., 2016). Variants in the text and tables should be presented at the DNA level, with the option of including (predicted) protein-based designations and RNA-based designations (when RNA is analyzed; see additional considerations below). Ideally, variants will be defined with respect to a specific genomic DNA reference sequence with a reference genome version clearly appended. The latest nomenclature updates, examples of acceptable nomenclature, and guidance concerning reference sequences can be found at https://varnomen.hgvs.org/.

  2. Compliance with HGVS nomenclature must be verified using tools such as the Mutalyzer program (https://mutalyzer.nl/; den Dunnen, 2016) or VariantValidator (https://variantvalidator.org/; Freeman et al., 2018) each of which offers a batch mode to facilitate rapid checking of multiple variant descriptions. Alternatively, variants previously submitted to existing online databases that ensure nomenclature compliance (e.g. ClinVar, LOVD), will have been assigned unique IDs by the database in question. Authors should include those unique IDs with the variants in their submitted manuscripts or provide a link retrieving the variant entries from the database.

  3. Authors must provide files generated by verification tools or database submission IDs to confirm that all variants comply with HGVS nomenclature.

  4. Editorial staff will review files provided by authors as a compliance check to confirm that authors used variant validation tools or have submitted their variants to a database that has validated the descriptions.

  5. Authors will be responsible for the accuracy of the variant description in their manuscripts, just as they are responsible for the accuracy of figures, tables, and data files.

3 |. IMPORTANT CONSIDERATIONS

Additional important considerations for clear and unambiguous documentation of variant descriptions include:

  • Reference sequences defined in the HGVS nomenclature guidelines (http://varnomen.hgvs.org/bg-material/refseq/) must be used to report sequence variants. Authors should always include the Accession and Version Number of the relevant reference sequence(s) (e.g., RefSeq NM_003002.3, LRG_9t1, or GenBank NC_000011.10) in the Materials and Methods section (or equivalent) and as a footnote in any tables listing variants.

  • If alternative nomenclature schemes are commonly found in the literature, they may also be used in addition to approved nomenclature, but they must be defined clearly and unambiguously (e.g., F5 p.Arg534Gln and factor V Leiden).

  • Standard HGVS nomenclature using “g.” annotation and identifying the genome build must be used for noncoding variants, including those variants identified in genome-wide association studies (GWAS; e.g., NC_000017.11:g.50201450C>T). Genomic location identifiers from dbSNP (https://www.ncbi.nlm.nih.gov/snp) may be added, in addition to approved nomenclature, if the specific nucleotide change is also included.

To assess the burden that these requirements may place on authors and editors, the staff of two journals, Human Mutation (www.wiley.com/humanmutation) and Genetics in Medicine (https://www.nature.com/gim/), performed a pilot project. We documented compliance with description requirements and recurrent issues over a period of 4 months. Concurrently, the staff who developed and implemented validation tools (Mutalyzer and VariantValidator) agreed to provide assistance to authors and to document unresolved issues.

Among 425 initial submissions to Human Mutation over a 6-month period from April 2019, 349 had variant data and over half (208) included the validation file. During the same time frame, 187 manuscripts under revision reported variants, of which 162 included a validation file, while the remaining 25 indicated that alternative validation software had been used or that variants had been previously reported. Genetics in Medicine (GIM) only checked revised manuscripts for variant data. Over a 3-month period, from April 2019, GIM received 193 revised manuscripts. Thirty-five of these contained variant data and all included a variant file. Four had to be sent back to the authors for errors to be corrected, but all revised manuscripts complied with the requirement to provide a file confirming that validation had been performed before the article was processed as a revision.

Several issues surfaced during the pilot project. Prime among these was the question of whether journal editors or authors should be responsible for correcting nomenclature errors. Two factors contributed to the committee’s response to this issue: (1) authors have primary responsibility for the accuracy of data presented in their publications; and (2) editorial staff do not have sufficient expertise or workforce capacity to perform these corrections. Therefore, the committee decided that authors should have final responsibility for correcting the nomenclature of any variants not conforming to HGVS guidelines. In addition, because a substantial fraction of published variants has documented nomenclature errors (e.g., Deans et al., 2016), the committee decided that all variants presented in a manuscript, whether new or previously reported, should be verified. This approach will progressively correct extant nomenclature errors. Mutalyzer and VariantValidator autocorrect variant descriptions and create warnings in their results file, except on rare occasions where there are syntax errors that cannot be interpreted/resolved. The HGVS nomenclature committee can assist when autocorrection does not occur (email to VarNomen@HGVS.org).

Upon reviewing the results of the pilot project, the committee agreed that requiring authors to verify that variants complied with HGVS nomenclature are a reasonable step toward standardizing the worldwide inventory of human variation. The editorial policy can require compliance with the recommendations to describe sequence variants adequately before manuscripts are accepted and published. Ideally, submission of variants and phenotypes to a public database before initial manuscript submission would streamline the review of manuscripts, by virtue of the intrinsic quality checks of compliant public databases (den Dunnen, 2019). Although we encourage immediate public sharing to support rapid use in the diagnosis, some databases (e.g., ClinVar and LOVD) allow an embargo period after data submission to allow for publication time. Finally, the process should not place an undue burden on editorial staff, as it only requires documentary evidence that authors have used the validation tools or have submitted their variants to a database that has validated the descriptions.

Issues that remain for editorial staff to consider for their own journals include the extent to which authors are required to correct nomenclature errors, guidelines for describing variants that cannot be defined using current HGVS description criteria, and manuscript types that may be exempt from description requirements. The committee recognized that a minor fraction of variants has ambiguous descriptions. Consequently, asking authors to provide documentation that errors could not be resolved after two attempts may be a reasonable compromise. In contrast, a lack of effort on the authors’ part to correct remediable errors may be considered as a reason to reject a manuscript.

4 |. CONCLUSION

The HVP/GV Reporting of Sequence Variants Working Group acknowledges that verifying descriptions of DNA variants using validation tools increases workload, albeit minor in most cases, for authors, and for editorial staff. However, we propose that the gain in accuracy outweighs the burden. Similar efforts in the past, such as verification of citations, have improved the robustness of scientific reports. Thus, we encourage all journal editors in human, medical and molecular genetics, and medical journals that frequently report disease-related variants to adopt these minimal recommendations. Table 1 lists the journals which to date have compliant editorial policies. These recommendations are fairly easy to implement, especially in modern editorial offices with automated submission systems and with technical support to editorial office staff from the database administrators. These recommendations will result in a vast improvement of the quality of variant description in the published literature.

TABLE 1.

Examples of journals that have editorial policies requiring validation of variant nomenclature and their author guidelines/policies

American Journal of Human Genetics https://www.cell.com/ajhg/authors
Cold Spring Harbor Molecular Case Studies http://molecularcasestudies.cshlp.org/site/misc/ifora_details.xhtml
European Journal of Human Genetics https://www.nature.com/ejhg/authors-and-referees/policies
European Journal of Medical Genetics https://www.elsevier.com/journals/european-journal-of-medical-genetics/1769-7212/guide-for-authors
Genetics in Medicine https://www.nature.com/gim/authors-and-referees
Human Genome Variation https://www.nature.com/documents/hgv-gta.pdf
Human Mutation https://onlinelibrary.wiley.com/page/journal/10981004/homepage/forauthors.html
Journal of Medical Genetics https://jmg.bmj.com/pages/authors/
Journal of Microbiology, Immunology and Infection https://www.elsevier.com/journals/journal-of-microbiology-immunology-and-infection/1684–1182/guide-for-authors
Journal of the Chinese Medical Association https://journals.lww.com/jcma/Pages/instructionstoauthors.aspx
Neuromuscular Disorders https://www.nmd-journal.com/content/authorinfo
Taiwan Journal of Ophthalmology http://www.e-tjo.org/contributors.asp
The Journal of Immunology https://www.jimmunol.org/info/authors
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ACKNOWLEDGMENTS

Patricia Cornwall for excellent assistance in the preparation of this manuscript; Robert D. Steiner, MD, Editor in Chief, Genetics in Medicine for framing editorial issues and expectations regarding this guidance. Support was provided by the National Human Genome Research Institute (U41HG006834 to Heidi L. Rehm) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK044003 to Garry R. Cutting) of the National Institutes of Health.

Footnotes

DISCLOSURES
  • Karen E. Weck: Unpaid conflicts: President, Association for Molecular Pathology.
  • Heidi L. Rehm, Garry R. Cutting: NIH funding for work related to this manuscript.
  • Johan T. DenDunnen: Cochair of HGVS nomenclature Sequence Variant Description Working Group (SVD-WG).
  • Peter J. Freeman: Colead on the VariantValidator project; Member of HGVS nomenclature Sequence Variant Description Working Group (SVD-WG).
  • Raymond Dalgleish: Nonfinancial conflicts: Codeveloper of VariantValidator; Member of the Board of Directors of HGVS; Member of HGVS nomenclature Sequence Variant Description Working Group (SVD-WG).

CONFLICT OF INTERESTS

These authors declare no conflict of interests: Jan Higgins, Li Gong, Teri E. Klein, David N. Cooper, Greg Barsh, Adya Misra, Issei Imoto, Peter J. Freeman, Johan T. den Dunnen, Juergen K.V. Reichardt, Bruce Korf, Katsushi Tokunaga, Huw Dorkins, Sarah Ratzel, Sara Cullinan, and Mark H. Paalman.

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