Generating Clinical-Grade Gene-Disease Validity Classifications Through the ClinGen Data Platforms.

Clinical genetic laboratories must have access to clinically validated biomedical data for precision medicine. A lack of accessibility, normalized structure, and consistency in evaluation complicates interpretation of disease causality, resulting in confusion in assessing the clinical validity of genes and genetic variants for diagnosis. A key goal of the Clinical Genome Resource (ClinGen) is to fill the knowledge gap concerning the strength of evidence supporting the role of a gene in a monogenic disease, which is achieved through a process known as Gene-Disease Validity curation. Here we review the work of ClinGen in developing a curation infrastructure that supports the standardization, harmonization, and dissemination of Gene-Disease Validity data through the creation of frameworks and the utilization of common data standards. This infrastructure is based on several applications, including the ClinGen GeneTracker, Gene Curation Interface, Data Exchange, GeneGraph, and website.

Enhancing Aotearoa, New Zealand's Free Healthline Service through Image Upload Technology.

Background: Healthline is one of the 39 free telehealth services that Whakarongorau Aotearoa/New Zealand Telehealth Services provides to New Zealanders. In early 2021, an image upload system for viewing service user-uploaded images was implemented into the Healthline service. Aims: The aim of this research was to understand the utilisation of Healthline's image upload system by clinicians and service users in New Zealand. Methods: This is a retrospective observational study analysing Healthline image upload data over a two-year period: March 2021 through to December 2022. A total of 40,045 images were analysed, including demographics of the service users who uploaded an image: ethnicity, age group, and area of residence. The outcome or recommendation of the Healthline call was also assessed based on whether an image was included. Results: Images uploaded accounted for 6.0% of total Healthline calls (n = 671,564). This research found that more service users were advised to go to an Emergency Department if they did not upload an image compared to service users who used the tool (13.5% vs. 7.7%), whereas a higher proportion of service users were given a lower acuity outcome if they included an image, including visiting an Urgent Care (24.0% vs. 16.9%) and GP (36.7% vs. 24.3%). Conclusion: Service users who did not upload an image had a higher proportion of Emergency Department outcomes than service users who did use the tool. This image upload tool has shown the potential to decrease stress on Emergency Departments around Aotearoa, New Zealand, through increased lower acuity outcomes.

Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Analysis of skin condition emergency department outcomes via the free Healthline service from Whakarongorau Aotearoa.

The aim of this research is to gain a deeper understanding of the ethnic and socio-demographic differences in the utilisation of the national 24/7 Healthline service in relation to skin condition calls and their outcomes. Healthline is one of the 39 free telehealth services that Whakarongorau Aotearoa | New Zealand Telehealth Services provides to New Zealanders. This is a retrospective observational study analysing Healthline data over a 4-year period: January 2019 through to December 2022. A total of 61,876 skin condition calls were analysed including demographics of service users: age group, ethnicity, area of residence and call outcome. Higher acuity skin condition calls resulting in an outcome of a recommendation for emergency department (ED) care accounted for 5.3% (n=3,294) of calls. This research found that Maori were over-represented in this ED recommendation data over four years (942 ED outcomes; 28.6%), and Pasifika were under-represented (203 ED outcomes; 5.9%). Wairarapa and West Coast were found to have the highest number of ED outcomes per capita. Our results support the theory that severe skin conditions positively correlate with smaller district populations and increased deprivation in access to services. This study highlights the potential that telehealth services have to help reduce the inequity of access to care.

Accessing clinical-grade genomic classification data through the ClinGen Data Platform.

The Clinical Genome Resource (ClinGen) serves as an authoritative resource on the clinical relevance of genes and variants. In order to support our curation activities and to disseminate our findings to the community, we have developed a Data Platform of informatics resources backed by standardized data models. In this workshop we demonstrate our publicly available resources including curation interfaces, (Variant Curation Interface, CIViC), supporting infrastructure (Allele Registry, Genegraph), and data models (SEPIO, GA4GH VRS, VA).

Whakarongorau abdominal pain review.

AIMS: The purpose of this study was to compare the frequency and profile of abdominal pain calls to Healthline with that from other national healthcare providers; to evaluate the outcomes for this symptom against international telehealth providers; and to explore any inter-clinician variation in the response to abdominal pain that could be part of a quality improvement cycle. METHODS: Data routinely collected about abdominal pain calls to Healthline from 2017 to 2019 were extracted, analysed; and compared to the literature, hospital, and ambulance data and international telehealth providers. A specialist group was convened to review the profile of Healthline callers and outcome data. Variation in outcome changes and acuity grouping was evaluated at an individual level. RESULTS: Approximately 50,000 abdominal pain calls to Healthline over three years were analysed, with three-quarters from women, mostly of childbearing age. The majority call afterhours, with NZ European and, to a lesser extent, Maori, and callers from smaller geographical areas are over-represented. One quarter of patients had a hospital outcome (including 4% receiving an ambulance), which was found to be less acute than comparable health systems. Whakarongorau's Clinical Governance Committee and the Specialist Group both supported the relative distribution of outcomes given by Healthline for abdominal pain. There was found to be variation in the outcomes given to abdominal pain callers at an individual clinician level. This was both in their changes to the disposition given by the Odyssey decision support tool and in their overall outcome distribution. CONCLUSION: Healthline should be considered a key part of New Zealand's healthcare system, as illustrated by the volume of calls that it receives and the fact that presentation types are similar to general practice and emergency departments. Given that abdominal pain is a difficult symptom to accurately address without in-person examination and investigation, the findings support Healthline's outcomes as appropriate with hospitalisation rates lower than comparable healthcare systems. Whakarongorau's (the organisation which runs Healthline) ability to identify individual clinician behaviours gives it a unique opportunity to improve care through decreasing variation.

ClinGen Variant Curation Interface: a variant classification platform for the application of evidence criteria from ACMG/AMP guidelines.

BACKGROUND: Identification of clinically significant genetic alterations involved in human disease has been dramatically accelerated by developments in next-generation sequencing technologies. However, the infrastructure and accessible comprehensive curation tools necessary for analyzing an individual patient genome and interpreting genetic variants to inform healthcare management have been lacking. RESULTS: Here we present the ClinGen Variant Curation Interface (VCI), a global open-source variant classification platform for supporting the application of evidence criteria and classification of variants based on the ACMG/AMP variant classification guidelines. The VCI is among a suite of tools developed by the NIH-funded Clinical Genome Resource (ClinGen) Consortium and supports an FDA-recognized human variant curation process. Essential to this is the ability to enable collaboration and peer review across ClinGen Expert Panels supporting users in comprehensively identifying, annotating, and sharing relevant evidence while making variant pathogenicity assertions. To facilitate evidence-based improvements in human variant classification, the VCI is publicly available to the genomics community. Navigation workflows support users providing guidance to comprehensively apply the ACMG/AMP evidence criteria and document provenance for asserting variant classifications. CONCLUSIONS: The VCI offers a central platform for clinical variant classification that fills a gap in the learning healthcare system, facilitates widespread adoption of standards for clinical curation, and is available at https://curation.clinicalgenome.org.

An Investigation of the Knowledge Overlap between Pharmacogenomics and Disease Genetics.

Precision medicine faces many challenges, including the gap of knowledge between disease genetics and pharmacogenomics (PGx). Disease genetics interprets the pathogenicity of genetic variants for diagnostic purposes, while PGx investigates the genetic influences on drug responses. Ideally, the quality of health care would be improved from the point of disease diagnosis to drug prescribing if PGx is integrated with disease genetics in clinical care. However, PGx genes or variants are usually not reported as a secondary finding even if they are included in a clinical genetic test for diagnostic purposes. This happens even though the detection of PGx variants can provide valuable drug prescribing recommendations. One underlying reason is the lack of systematic classification of the knowledge overlap between PGx and disease genetics. Here, we address this issue by analyzing gene and genetic variant annotations from multiple expert-curated knowledge databases, including PharmGKB, CPIC, ClinGen and ClinVar. We further classified genes based on the strength of evidence supporting a gene's pathogenic role or PGx effect as well as the level of clinical actionability of a gene. Twenty-six genes were found to have pathogenic variation associated with germline diseases as well as strong evidence for a PGx association. These genes were classified into four sub-categories based on the distinct connection between the gene's pathogenic role and PGx effect. Moreover, we have also found thirteen RYR1 genetic variants that were annotated as pathogenic and at the same time whose PGx effect was supported by a preponderance of evidence and given drug prescribing recommendations. Overall, we identified a nontrivial number of gene and genetic variant overlaps between disease genetics and PGx, which laid out a foundation for combining PGx and disease genetics to improve clinical care from disease diagnoses to drug prescribing and adherence.

Evaluating the impact of in silico predictors on clinical variant classification.

PURPOSE: According to the American College of Medical Genetics and Genomics/Association of Medical Pathology (ACMG/AMP) guidelines, in silico evidence is applied at the supporting strength level for pathogenic (PP3) and benign (BP4) evidence. Although PP3 is commonly used, less is known about the effect of these criteria on variant classification outcomes. METHODS: A total of 727 missense variants curated by Clinical Genome Resource expert groups were analyzed to determine how often PP3 and BP4 were applied and their impact on variant classification. The ACMG/AMP categorical system of variant classification was compared with a quantitative point-based system. The pathogenicity likelihood ratios of REVEL, VEST, FATHMM, and MPC were calibrated using a gold standard set of 237 pathogenic and benign variants (classified independent of the PP3/BP4 criteria). RESULTS: The PP3 and BP4 criteria were applied by Variant Curation Expert Panels to 55% of missense variants. Application of those criteria changed the classification of 15% of missense variants for which either criterion was applied. The point-based system resolved borderline classifications. REVEL and VEST performed best at a strength level consistent with moderate evidence. CONCLUSION: We show that in silico criteria are commonly applied and often affect the final variant classifications. When appropriate thresholds for in silico predictors are established, our results show that PP3 and BP4 can be used at a moderate strength.

Whakarongorau Aotearoa: insight into the delivery of New Zealand's national telehealth services.

Whakarongorau Aotearoa/New Zealand Telehealth Services, formerly known as Homecare Medical, is New Zealand's largest digital healthcare service. It originated as a house call doctor service about 20 years ago and now delivers free 24/7 telehealth services to the New Zealand public 365 days a year. Whakarongorau Aotearoa changed its name in April 2021 to reflect the growing kaupapa and was gifted this whakatauki: He reo marohirohi ka taringa rongohia-A brave voice deserves a listening ear. This viewpoint sets out to address a number of public and professional misconceptions about Whakarongorau Aotearoa and provide a more detailed description of the depth, breadth and complexity of the organisation, how it is structured, the range of services available to the public and its clinical governance, leadership and oversight.

Time-Averaged Wavefront Analysis Demonstrates Preferential Pathways of Atrial Fibrillation, Predicting Pulmonary Vein Isolation Acute Response.

Electrical activation during atrial fibrillation (AF) appears chaotic and disorganised, which impedes characterisation of the underlying substrate and treatment planning. While globally chaotic, there may be local preferential activation pathways that represent potential ablation targets. This study aimed to identify preferential activation pathways during AF and predict the acute ablation response when these are targeted by pulmonary vein isolation (PVI). In patients with persistent AF (n = 14), simultaneous biatrial contact mapping with basket catheters was performed pre-ablation and following each ablation strategy (PVI, roof, and mitral lines). Unipolar wavefront activation directions were averaged over 10 s to identify preferential activation pathways. Clinical cases were classified as responders or non-responders to PVI during the procedure. Clinical data were augmented with a virtual cohort of 100 models. In AF pre-ablation, pathways originated from the pulmonary vein (PV) antra in PVI responders (7/7) but not in PVI non-responders (6/6). We proposed a novel index that measured activation waves from the PV antra into the atrial body. This index was significantly higher in PVI responders than non-responders (clinical: 16.3 vs. 3.7%, p = 0.04; simulated: 21.1 vs. 14.1%, p = 0.02). Overall, this novel technique and proof of concept study demonstrated that preferential activation pathways exist during AF. Targeting patient-specific activation pathways that flowed from the PV antra to the left atrial body using PVI resulted in AF termination during the procedure. These PV activation flow pathways may correspond to the presence of drivers in the PV regions.

Quality of life and healthcare utilisation improvements after atrial fibrillation ablation.

OBJECTIVE: Pulmonary vein isolation (PVI) guided by a standardised CLOSE (contiguous optimised lesions) protocol has been shown to increase clinical success after catheter ablation for paroxysmal atrial fibrillation (PAF). This study analysed healthcare utilisation and quality of life (QOL) outcomes from a large multicentre prospective study, measured association between QOL and atrial fibrillation (AF) burden and identified factors associated with lack of QOL improvement. METHODS: CLOSE-guided ablation was performed in 329 consecutive patients (age 61.4 years, 60.8% male) with drug-refractory PAF in 17 European centres. QOL was measured at baseline and 12 months post-ablation via Atrial Fibrillation Effect on QualiTy of Life Survey (AFEQT) and EuroQoL EQ-5D-5L questionnaires. All-cause and cardiovascular hospitalisations and cardioversions over 12 months pre-ablation and post-ablation were recorded. Rhythm monitoring included weekly and symptom-driven trans-telephonic monitoring, plus ECG and Holter monitoring at 3, 6 and 12 months. AF burden was defined as the percentage of postblanking tracings with an atrial tachyarrhythmia ≥30 s. Continuous measures across multiple time points were analysed using paired t-tests, and associations between various continuous measures were analysed using independent sample t-tests. Each statistical test used two-sided p values with a significance level of 0.05. RESULTS: Both QOL instruments showed significant 12-month improvements across all domains: AFEQT score increased 25.1-37.5 points and 33.3%-50.8% fewer patients reporting any problem across EuroQoL EQ-5D-5L domains. Overall, AFEQT improvement was highly associated with AF burden (p=0.009 for <10% vs ≥10% burden, p<0.001 for <20% vs ≥20% burden). Cardiovascular hospitalisations were significantly decreased after ablation (42%, p=0.001). Patients without substantial improvement in AFEQT (55/301, 18.2%) had higher AFEQT and CHA2DS2-VASc scores at baseline, and higher AF burden following PVI. CONCLUSIONS: QOL improved and healthcare utilisation decreased significantly after ablation with a standardised CLOSE protocol. QOL improvement was significantly associated with impairment at baseline and AF burden after ablation. TRIAL REGISTRATION NUMBER: NCT03062046.

OpenEP: A Cross-Platform Electroanatomic Mapping Data Format and Analysis Platform for Electrophysiology Research.

BACKGROUND: Electroanatomic mapping systems are used to support electrophysiology research. Data exported from these systems is stored in proprietary formats which are challenging to access and storage-space inefficient. No previous work has made available an open-source platform for parsing and interrogating this data in a standardized format. We therefore sought to develop a standardized, open-source data structure and associated computer code to store electroanatomic mapping data in a space-efficient and easily accessible manner. METHODS: A data structure was defined capturing the available anatomic and electrical data. OpenEP, implemented in MATLAB, was developed to parse and interrogate this data. Functions are provided for analysis of chamber geometry, activation mapping, conduction velocity mapping, voltage mapping, ablation sites, and electrograms as well as visualization and input/output functions. Performance benchmarking for data import and storage was performed. Data import and analysis validation was performed for chamber geometry, activation mapping, voltage mapping and ablation representation. Finally, systematic analysis of electrophysiology literature was performed to determine the suitability of OpenEP for contemporary electrophysiology research. RESULTS: The average time to parse clinical datasets was 400 ± 162 s per patient. OpenEP data was two orders of magnitude smaller than compressed clinical data (OpenEP: 20.5 ± 8.7 Mb, vs clinical: 1.46 ± 0.77 Gb). OpenEP-derived geometry metrics were correlated with the same clinical metrics (Area: R 2 = 0.7726, P < 0.0001; Volume: R 2 = 0.5179, P < 0.0001). Investigating the cause of systematic bias in these correlations revealed OpenEP to outperform the clinical platform in recovering accurate values. Both activation and voltage mapping data created with OpenEP were correlated with clinical values (mean voltage R 2 = 0.8708, P < 0.001; local activation time R 2 = 0.8892, P < 0.0001). OpenEP provides the processing necessary for 87 of 92 qualitatively assessed analysis techniques (95%) and 119 of 136 quantitatively assessed analysis techniques (88%) in a contemporary cohort of mapping studies. CONCLUSIONS: We present the OpenEP framework for evaluating electroanatomic mapping data. OpenEP provides the core functionality necessary to conduct electroanatomic mapping research. We demonstrate that OpenEP is both space-efficient and accurately representative of the original data. We show that OpenEP captures the majority of data required for contemporary electroanatomic mapping-based electrophysiology research and propose a roadmap for future development.

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures.

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (n = 448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research.

Benefits of effective multidisciplinary teamwork: catheter ablation of premature ventricular ectopics.

The case concerns a difficult but successful right ventricular outflow tract ectopy catheter ablation in a fit and well 33-year-old man with a 16-year history of symptomatic premature ventricular contractions (PVCs). Beta blockade medication had become ineffective in suppressing the PVCs, and a 24-hour Holter monitor revealed a high burden of ectopy (10%). An echocardiogram and cardiac MRI showed a structurally normal heart. During the procedure, it became impossible to uncurve the catheter, and it lodged in the patient's right femoral artery. Immediate collaboration with interventional cardiology and interventional radiology was required to resolve the issue. The case demonstrates that excellent teamwork and calling rapidly on input from subspecialties are integral to overcoming unexpected events and to achieve a safe and successful outcome. The patient involved was a medical student at the time and as one of the coauthors offers a unique insight.

LitGen: Genetic Literature Recommendation Guided by Human Explanations.

As genetic sequencing costs decrease, the lack of clinical interpretation of variants has become the bottleneck in using genetics data. A major rate limiting step in clinical interpretation is the manual curation of evidence in the genetic literature by highly trained biocurators. What makes curation particularly time-consuming is that the curator needs to identify papers that study variant pathogenicity using different types of approaches and evidences-e.g. biochemical assays or case control analysis. In collaboration with the Clinical Genomic Resource (ClinGen)-the flagship NIH program for clinical curation-we propose the first machine learning system, LitGen, that can retrieve papers for a particular variant and filter them by specific evidence types used by curators to assess for pathogenicity. LitGen uses semi-supervised deep learning to predict the type of evi+dence provided by each paper. It is trained on papers annotated by ClinGen curators and systematically evaluated on new test data collected by ClinGen. LitGen further leverages rich human explanations and unlabeled data to gain 7.9%-12.6% relative performance improvement over models learned only on the annotated papers. It is a useful framework to improve clinical variant curation.

Analysis of presenting symptoms and diagnoses made at Middlemore Hospital: an audit carried out between Monday 1 August and Sunday 7 August 2016.

AIMS: Perform an audit which identifies the breadth and commonality of presenting complaints and diagnoses presenting to Middlemore Hospital over a one-week period in August 2016. METHODS: Two thousand and eleven patients attended Middlemore Hospital over one week in winter 2016, with 53 patients excluded. Information from the remaining 1,958 patient discharge summaries were obtained and made confidential for coding purposes. RESULTS: Of 1,958 patients, there were 78 different presenting complaints, with 444 individual final diagnoses. The five most common complaints were cough (n=158, 8.1%), chest pain (n=133, 6.8%), shortness of breath (n=92, 4.7%), finger pain (n=69, 3.5%) and collapse (n=59, 3.0%). Viral illness (n=84, 4.3%), pneumonia (n=83, 4.3%) and laceration/incised wound (n=75, 3.8%) were the three most common diagnoses. With hindsight, only 2 of the 25 most common diagnoses could be classified as severe conditions-often associated with high morbidity or mortality. CONCLUSIONS: Numerous patients are diagnosed with mild conditions after work-up in the emergency department, however a broad diagnostic approach is required by junior clinicians given the possibility of more worrying diagnoses. An analysis of specific markers used by junior clinicians to aid differential diagnosis shows that not all signs and symptoms are required to make common diagnoses. For example, the absence of a documented fever, raised CRP or both, does not rule out significant infection in the case of pneumonia, urinary tract infection and cellulitis. This audit contributes to understanding the case-mix within the emergency department at Middlemore Hospital and allows for tailoring of service delivery and education of junior clinicians.

Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework.

BACKGROUND: The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) clinical variant interpretation guidelines established criteria for different types of evidence. This includes the strong evidence codes PS3 and BS3 for "well-established" functional assays demonstrating a variant has abnormal or normal gene/protein function, respectively. However, they did not provide detailed guidance on how functional evidence should be evaluated, and differences in the application of the PS3/BS3 codes are a contributor to variant interpretation discordance between laboratories. This recommendation seeks to provide a more structured approach to the assessment of functional assays for variant interpretation and guidance on the use of various levels of strength based on assay validation. METHODS: The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation (SVI) Working Group used curated functional evidence from ClinGen Variant Curation Expert Panel-developed rule specifications and expert opinions to refine the PS3/BS3 criteria over multiple in-person and virtual meetings. We estimated the odds of pathogenicity for assays using various numbers of variant controls to determine the minimum controls required to reach moderate level evidence. Feedback from the ClinGen Steering Committee and outside experts were incorporated into the recommendations at multiple stages of development. RESULTS: The SVI Working Group developed recommendations for evaluators regarding the assessment of the clinical validity of functional data and a four-step provisional framework to determine the appropriate strength of evidence that can be applied in clinical variant interpretation. These steps are as follows: (1) define the disease mechanism, (2) evaluate the applicability of general classes of assays used in the field, (3) evaluate the validity of specific instances of assays, and (4) apply evidence to individual variant interpretation. We found that a minimum of 11 total pathogenic and benign variant controls are required to reach moderate-level evidence in the absence of rigorous statistical analysis. CONCLUSIONS: The recommendations and approach to functional evidence evaluation described here should help clarify the clinical variant interpretation process for functional assays. Further, we hope that these recommendations will help develop productive partnerships with basic scientists who have developed functional assays that are useful for interrogating the function of a variety of genes.

ClinGen Allele Registry links information about genetic variants.

Effective exchange of information about genetic variants is currently hampered by the lack of readily available globally unique variant identifiers that would enable aggregation of information from different sources. The ClinGen Allele Registry addresses this problem by providing (1) globally unique "canonical" variant identifiers (CAids) on demand, either individually or in large batches; (2) access to variant-identifying information in a searchable Registry; (3) links to allele-related records in many commonly used databases; and (4) services for adding links to information about registered variants in external sources. A core element of the Registry is a canonicalization service, implemented using in-memory sequence alignment-based index, which groups variant identifiers denoting the same nucleotide variant and assigns unique and dereferenceable CAids. More than 650 million distinct variants are currently registered, including those from gnomAD, ExAC, dbSNP, and ClinVar, including a small number of variants registered by Registry users. The Registry is accessible both via a web interface and programmatically via well-documented Hypertext Transfer Protocol (HTTP) Representational State Transfer Application Programming Interface (REST-APIs). For programmatic interoperability, the Registry content is accessible in the JavaScript Object Notation for Linked Data (JSON-LD) format. We present several use cases and demonstrate how the linked information may provide raw material for reasoning about variant's pathogenicity.