Golden Helix’s Recent Release for a New Workflow for Interpretating and Reporting Copy Number Variants in Concordance with the Recently Updated ACMG Guidelines:  Introduction

by Dr. Andreas Scherer, President & CEO of Golden Helix

A copy number variation (CNV) is a type of structural variation in which a large section of the genome is either duplicated or deleted. CNVs account for much of the variation between human genomes, and they are associated with a wide range of disorders. As more disorders associated with CNVs are identified, and as NextGen sequencing is more widely utilized in the clinical setting, tools supporting rapid, accurate, and cost-effective identification and interpretation of CNVs are needed.

Recently, the American College of Medical Genetics and Genomics (ACMG) has developed a new set of CNV interpretation guidelines in collaboration with the Clinical Genome Resource (ClinGen) project,1 analogous to the guidelines currently in place for small variants. In the time since the release of these guidelines, the Golden Helix team has developed a new automated workflow that enables clinical labs to implement these guidelines consistently and efficiently. This workflow is the first commercial solution supporting the new CNV guidelines to reach the market and has been developed through repeated correspondence with the authors of the original paper.

This workflow guides the clinician through every step of the CNV interpretation process. Using state-of-the-art algorithms, our workflow automatically evaluates a CNV’s impact on a given gene and provides powerful tools for reviewing literature to gather evidence supporting or refuting a gene’s dosage sensitivity. Using our powerful annotation engine, the clinician can quickly determine if a given CNV overlaps common population variations in 1000 Genomes or GnomAD and can quickly identify previously classified variants in both ClinVar and your own internal database. Once the interpretation process is complete, you can generate beautiful and customizable clinical reports using our new MS Word templating system.

Along with CNVs, these reports can contain variants scored with our existing VSClinical ACMG guidelines workflow and other supporting NGS summary and QC details. Finally, all evidence associated with evaluated CNVs and genes can be saved to a central database for reuse in future clinical interpretations.

Background on the CNV Guidelines and Relevant Changes
While the previous version of the CNV guidelines was primarily focused on the interpretation of large cytogenetic events, the updated guidelines and technical standards1a,1b provide robust standards for the interpretation of small intragenic CNVs in addition to large multi-gene events. The new guidelines classify variants according to the same 5-tier classification system that is used for the interpretation of small sequence variants1c,1d and uncouples the classification of a CNV’s pathogenicity from itsimplications for any individual.

The process of classifying a CNV that impacts a single gene in accordance with these guidelines addresses two important questions. First, the clinician must assess whether any overlapping genes or genomic regions have been established to be either haploinsufficient (in case of deletions and intragenic duplications) or triplosensitive (in the case of whole-gene duplications). To aid clinicians in the identification of such genes, ClinGen has developed the Dosage Sensitivity Map, a publicly available resource cataloging the evidence for the dosage sensitivity of genes and genomic regions. However, CNVs often overlap genes that have not been previously evaluated for dosage sensitivity. In these cases, the clinician must review the available literature to determine whether a given gene is likely to be either haploinsufficient or triplosensitive. Sections 4 and 5 of the new CNV guidelines1b describe specific rules for making this determination.

Once it has been determined that a given CNV overlaps a confirmed haploinsufficient or triplosensitive region, the clinician must then evaluate the CNV’s impact on the gene. Forduplications of triplosensitive genes, this process simply involves verifying that the entire coding region of the gene is duplicated. For intragenic CNVs within established haploinsufficient genes, however, the process is more complicated and involves many differentconsiderations, such as:

◆ The variant’s effect on the reading frame
◆ The variant’s proximity to the 3’ end of the gene
◆ The variant’s overlap with previously established benign CNVs

For more detail on these points, see Section 2 of the new CNV guidelines,1b which describes the process for scoring a CNV based on its impact on the gene. In summary, new information needs new tools to assess patient genetic information, especially in light of ClinGen’s release of new standards and guidelines. Golden Helix tackled the task of making this information accessible to clinicians with its recently released VSClinical and its portfolio of tools that meet this challenge. A technical article by Golden Helix will be forthcoming in the March issue of the Journal – be sure to watch for it then.

Dr. Andreas Scherer is CEO of Golden Helix. The company has been delivering industry-leading bioinformatics solutions for the advancement of life science research and translational medicine for over two decades. Its innovative technologies and analytic services empower clinicians and scientists at alllevels to derive meaning from the rapidly increasing volumes of genomic data produced from next-generation sequencing and microarrays. With its solutions, hundreds of the world’s hospitals, testing labs, academic research organizations, and governments are able to harness the full potential of genomics to identify the cause of disease,develop genomic diagnostics, and advance the quest for personalized medicine. Golden Helix products and services have been cited in thousands of peer-reviewedpublications.


1. a. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) • See also:
b. Copy Number Variant Interpretation Guidelines •
c. Riggs, Erin Rooney, et al. “Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen).” • Genetics in Medicine 22.2 (2020): 245-257.
d. Richards, Sue, et al. “Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.” • Genetics in medicine 17.5 (2015): 405-423.