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.

Health and population effects of rare gene knockouts in adult humans with related parents

“…audiometry for deafness genotypes). However in support of the general significance of our findings, markedly reduced penetrance estimates have been shown for Mendelian forms of diabetes when taken from population samples (13), and the ClinGen study identified an initial set of variants annotated as pathogenic in OMIM (220 of ~25,000 entries) but now thought to be benign or of uncertain significance (14). In the ClinSeq cohort, with an older age of ascertainment, 45 of 73 individuals with rare heterozygous LOF in a gene that had been reported to cause disease via dominant LOF alleles did not have the expected phenotype (15).…”

Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics

“…The SFWG acknowledged the inherent subjectivity and difficulty of rating any given intervention as it applies to an individual but voted unanimously in favor of adding this fifth criterion. This achieved consistency with efforts of the NIH-funded Clinical Genome Resource (ClinGen) 5 Actionability Working Group, 6 which had already applied these five criteria to assign actionability scores (called "Actionability Evidence-based Summaries") 7 to genes/conditions on the SF list.…”

Variant Interpretation: Functional Assays to the Rescue

“…Significant effort has already gone into identifying actionable genes, 24 and these genes should have the highest priority. For example, the American College of Medical Genetics (ACMG) identified 59 genes in which pathogenic variants are actionable 25,26 and recommends that incidentally discovered pathogenic variants in these genes be returned to the individual.…”

“…24,27,81,82 These models incorporate various types of evidence, including phenotype and family history, pathology and clinical testing data (e.g., imaging and echocardiography), allelic observations (i.e., the co-occurrence of variants in cis or trans), familial segregation and de novo occurrence, data on population frequency, functional assays, and predictive algorithms. Ultimately, MAVE-derived probabilities of pathogenicity could be incorporated into these models as well.…”