ClinGen--the Clinical Genome Resource

Abstract

On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography. Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as “likely benign” by another laboratory that uses more recently derived population-frequency data. A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic. Family members are retested, and one member who previously tested negative is now found to be positive for this new variant. An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death.

Figure 1. Variant Histogram from Mendelian Disease Testing of 15,000 Probands

Shown are data for 5839 variants that have been found in patients with cardiomyopathy, hearing loss, RASopathies (i.e., developmental syndromes caused by germline mutations that alter the Ras subfamily), aortopathies, hereditary cancers, pulmonary disorders, skin disorders, and other genetic syndromes, as tested by the Laboratory for Molecular Medicine at Partners HealthCare. Shown at the top of the chart are the percentages of patients who carry frequently observed pathogenic variants and patients who have variants that are rare or of uncertain significance.

Figure 2. Clinical Genome Resource (ClinGen)

More information on ClinGen is available at www.clinicalgenome.org, and more information on ClinVar is available at www.ncbi.nlm.nih.gov/clinvar.

Figure 3. Flow of Data through ClinGen

Shown is the typical flow of information into ClinVar and ClinGenKB, a new database that is designed to allow for a flexible working environment for curation. Most variants are submitted by external sources and databases directly into ClinVar for immediate access by the community. Variants then flow into ClinGenKB to enable the resolution of differences in interpretation, as well as expert review of variants by the clinical-domain working groups that are shown. Additional sources of data and machine-learning algorithms may be brought into ClinGenKB to aid in the interpretive process. BIC denotes Breast Cancer Information Core, CFTR2 Clinical and Functional Translation of CFTR, InSiGHT the variant database for the International Society for Gastrointestinal Hereditary Tumours, OMIM Online Mendelian Inheritance in Man, and PharmGKB the Pharmacogenomics Knowledge Base.

Figure 4. Review Levels Annotated in ClinVar

Variants with assertions are rated according to the source and level of review for each submitted variant assertion. Submitters must comply with requirements (www.ncbi.nlm.nih.gov/clinvar/docs/assertion_criteria) for a submission to be assigned one, three, or four stars. Two stars are automatically assigned when multiple one-star submitted assertions are consistent. The distinction between submitters that have provided criteria and those that have not will begin in June 2015.