Towards robust clinical genome interpretation: developing a consistent terminology to characterize disease-gene relationships - allelic requirement, inheritance modes and disease mechanisms

PURPOSE The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation, and to support variant classification within the ACMG/AMP framework. METHODS Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition (GenCC) members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both sequence ontology (SO) and human phenotype ontology (HPO) ontologies. GenCC member groups intend to use or map to these terms in their respective resources. CONCLUSION The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation. ### Competing Interest Statement J.S.W. has received research support or consultancy fees from Myokardia, Bristol-Myers Squibb, Pfizer, and Foresite Labs ### Funding Statement This work was supported by the Sir Jules Thorn Trust [21JTA], Wellcome Trust [107469/Z/15/Z; 200990/A/16/Z; 222883/Z/21/Z], Medical Research Council (UK), British Heart Foundation [RE/18/4/34215; FS/CRLF/21/23011], NHLI Foundation Royston Centre for Cardiomyopathy Research, and the NIHR Imperial College Biomedical Research Centre. MTD was supported by the National Human Genome Research Institute grant U24HG006834. JSB was supported by the National Human Genome Research Institute grant U24HG009650. FC was supported by the European Molecular Biology Laboratory. JF and DP were supported by Wellcome [grant number WT223718/Z/21/Z and 220540/Z/20/A Wellcome Sanger Institute Quinquennial Review 2021-2026]. CLM was supported by the National Human Genome Research Institute grant U24HG006834. ERR was supported by the National Human Genome Research Institute grant U24HG006834. PNR was supported by the National Human Genome Research Institute grant U24HG011449. David van Sant was funded by NIH: T15LM007124. PanelApp Australia is funded by Australian Genomics (NHMRC grants GNT1113531 and GNT2000001). NW is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (220134/Z/20/Z) and the Rosetrees Trust (PGL19-2/10025). HLR was supported by the National Human Genome Research Institute grant U24HG006834. Open Targets is supported by Open Targets. The work performed by authors at European Molecular Biology Laboratory-European Bioinformatics Institute for the Transforming Genomic Medicine Initiative project was supported by the Wellcome Trust (WT200990/Z/16/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript, supplement and online at https://github.com/ImperialCardioGenetics/ACMGSF\_pilot\_curation/ [https://github.com/ImperialCardioGenetics/ACMGSF\_pilot\_curation/][1] [1]: https://github.com/ImperialCardioGenetics/ACMGSF_pilot_curation/