Impact case study database

VariantValidator is the cumulative result of decades of research, expertise, and development of human genome sequence variation data, by Dalgleish and his team, providing solutions to major obstacles in treatment-programme development using genetic information. The beneficiaries range from individual parties (patients and healthcare professionals) to multinational organisations and research programmes. VariantValidator has defined the future direction for interpretation of genetic sequencing by simultaneously ensuring future NHS Clinical Scientists are trained to far higher standards, and by significantly reducing potentially catastrophic errors in scientific research outputs being made, disseminated or repeated. VariantValidator is the global gold-standard HGVS variant nomenclature validation software.

Freely available, the open access VariantValidator software supports data handling and validation in field-leading organisations worldwide. Between launch in 2016 and 2020, VariantValidator had been used ~55,000 times by 40,451 unique users from 118 countries, with total user numbers increasing rapidly each year [E1].

Example organisations who have embraced VariantValidator include:

• GEL: Responsible for delivering 100,000 Genomes Project [E2a]

• ClinVar: US National Institutes for Health database used globally for sequence variation interpretation [E3]

• Catalogue Of Somatic Mutations In Cancer (COSMIC): The world’s largest and most comprehensive resource for exploring the impact of somatic mutations in cancer [E2b]

• Laboratoire de Génétique Moléculaire, CHU de Montpellier, France: have developed a variant annotation and interpretation software platform (MobiDetails) for which the variant validation engine of VariantValidator is a central embedded component [E4]

• European Bioinformatics Institute: International Non-Governmental Organisation providing bioinformatics services, training, and resources to the science community globally [E5]

In each case, and countless others, VariantValidator has consistently demonstrated its superiority over competitors, “ similar systems known to us do not provide the modularity, code libraries or lack some key functionality” GEL [E2a], and is now built into workflows facilitating high-impact biomedical research [E6] through substantially improved accuracy, efficiency, and usability. VariantValidator reduces genome coordinate mapping time from ~60 minutes per case to ~3 minutes [E2c]. In many leading organisations VariantValidator has replaced existing tools or is the preferred sequence variation curation tool including:

• Global Alliance for Genomics and Health (GA4GH)

• Centre for Medical Genetics, Brussels, Belgium [E2d]

• Leiden Open Variation Database (LOVD) [E2e]

• London South Genomics Laboratory Hub, North West Genomic Laboratory Hub, and other NHS laboratories

• The Manchester Academy for Healthcare Scientist Education (MAHSE) training programmes in medical genomics and genomics bioinformatics

• Global PGCert, and MSc courses delivered by the University of Manchester [E8]

• Center for Genomics Interpretation, Utah, USA [E2f]

The widespread response to the software has been immensely positive with many echoing Professor Robinson of the Jackson Laboratory, “We have also used what is probably VariantValidator’s main competitor, Mutalyzer, but have chosen to use VariantValidator for our work because of the substantially greater amount of information presented to the user, the ease of use and the flexibility of the API and paramaterized URLs and the much better graphical user interface, all of which improves the efficiency of our work”’ [E2c]. At the Centre for Medical Genetics, Brussels, “ VariantValidator has been indispensable” and they “ are now validating thousands of variants every week with VariantValidator” [E2d].

New HGVS Variant Nomenclature recommendations have recently been developed by PF and RD to accommodate the use of Ensembl transcript reference sequences for variant reporting [E9]. This enables NHS laboratories, for the first time, to utilise genome sequencing variant data, generated by GEL. This novel development is being incorporated into a new reference sequence transcript archive that is, in direct collaboration with GEL and LOVD, being integrated into VariantValidator. The purpose of this development is to produce a tool enabling GEL processing to provide NHS laboratories with correctly formatted variant descriptions in the context of Ensembl reference sequences and enabling LOVD to accommodate Ensembl transcript data alongside existing RefSeq data. “At present, we are unable to do this for the RefSeq datasets which is an unmet requirement for reporting in the clinical setting. This is a common requirement among clinicians to facilitate interpretation of genomic variation.” GEL [E2a]. Immediate beneficiaries of this development include the GEL 100,000 Genomes Project [E2a], COSMIC [E3] and a wider set of NHS Genomics Laboratory Hubs who will soon be able to validate and safely share their variant data outputs.

Collaboration between the University of Leicester and GEL has also resulted in the development of VariantFormatter software libraries enabling GEL to correctly present data using HGVS nomenclature. This system rapidly validates HGVS descriptions in the context of genomic reference sequences projecting them rapidly onto all relevant transcripts. In addition, the VariantValidator tool enables improved accuracy in variant descriptions for use in clinical reports and databases, lift-overs between Ensembl and pre-existing reference sequences, and interconversions between transcript and genomic-coordinate-based descriptions [E2a]. In addition, a novel version of the VariantFormatter tool has been created to produce accurately formatted data for the LOVD databases, and alongside VariantValidator, is being embedded directly into the LOVD analysis pipelines. This will have a huge impact on genomic medicine in Europe where LOVD is rapidly becoming a staple platform, replacing commercial solutions in diagnostic settings [E10].

The proven superiority of VariantValidator has changed industry direction. Since 2017, Alamut Visual, the flagship software product from SOPHiA Genetics, has incorporated links to VariantValidator to allow users of their software to ensure accurate validation of sequence variant descriptions and have recently installed the VariantValidator code on their servers for internal use [E8]. VariantValidator has also been adopted as the variant description validation program and interconversion tool of choice for the Global Alliance for Genomics and Health (GA4GH) ‘PhenoPackets’ and ‘Solving the Unsolved Rare Diseases’ (SOLVE-RD) projects [E6], is a key component of the Jackson Laboratory’s new HPO-based phenotype annotation software; HPOCaseAnnotator [E11], and is used as standard practice by the Center for Genomic Interpretation in Utah to improve their clinical reporting [E2f].

VariantValidator is having a profound impact on education in genomic bioinformatics, primarily in the UK, but also to a global audience. VariantValidator’s demonstrable success convinced the Manchester Academy for Healthcare Scientist Training (MAHSE) to incorporate the software into NHS Scientist Training Programmes (STP) that contain genomics-focused modules, in 2019. VariantValidator is now taught to NHS STP MSc Students in Clinical Genetics, Clinical Bioinformatics, Health Informatics, Cancer Genomics, Medical Physics, and Genomic Counselling. Over 150 students are trained annually using the software leading to a wider deployment in NHS Clinical Genomics Centres and Genetics Diagnostics Laboratories. As well as learning to use VariantValidator, the course also enables students to produce additional resources for the system thereby enabling continuous resource growth and improvement alongside the internationally praised training scheme [E8]. This training not only provides VariantValidator with a direct pathway into clinical practice, and establishes a community of practice who not only use the software, but also steer future iterations of the software to meet the evolving needs of the genomic medicine community.

VariantValidator is embedded into healthcare professional CPD courses ‘Fundamentals in Human Genetics and Genomics’ funded by Health Education England and taught at the University of Manchester [E12]. VariantValidator is also embedded into the ‘first of its kind’ distance-learning Postgraduate Certificate in Clinical Bioinformatics [E13]. The current run of the course includes 37 students from around the world from a broad range of professions, including clinicians in non-UK diagnostics laboratories and the Qatari genome project. The success of the 2019 PGCert was disseminated to audiences in international educational symposia as evidenced in a University of Manchester blog article [E8]. VariantValidator is also embedded into the MSc in Genomic Medicine at the University of Manchester.

In 2020, following a successful pilot published by Human Mutation (Wiley) and Genetics in Medicine (Nature), several leading biomedical journals formally adopted VariantValidator as one of two approved validation tools to ensure correctness of variant descriptions in published manuscripts and to minimise errors long-term [E14]. This critical change in professional practice has already yielded benefits to patients, including successfully identifying and correcting multiple invalid and incorrect sequence descriptions previously used to define treatment for cystic fibrosis patients: “ These efforts will undoubtedly lead to tangible improvements in patient care” [E2g].