Golden Helix Announces New Workflow for the Interpretation and Reporting of Copy Number Variants in Concordance with the Recently Updated ACMG Guidelines

         August 18, 2020

The detection and interpretation of Copy Number Variants (CNVs) is vital for the clinical evaluation of individuals with a wide range of disorders. Golden Helix has remained at the forefront of CNVs in Next-Gen Sequencing (NGS) data since 2016 with the release of VS-CNV, our solution that allows you to both detect and analyze CNVs directly from NGS data.

Earlier this year, the American College of Medical Genetics and Genomics (ACMG) developed a new set of professional guidelines in collaboration with the Clinical Genome Resource (ClinGen) project [1], analogous to the guidelines currently in place for SNPs. Over the last several months, our team has been diligently working on a new guided workflow that will allow clinical labs to implement these guidelines consistently and efficiently. This workflow guides the clinician through every step of the CNV interpretation process and is in complete agreeance with the authors of this paper on how this should look from a software perspective.

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.

We are looking forward to making this workflow available to our community in the fall. You can expect to see additional information on the release in the coming weeks, including our next webcast, as well as introductory pricing for this workflow which you can find more information on here.

Learn More About the Changes Made to the CNV Guidelines

While the previous version of the CNV guidelines was primarily focused on the interpretation of large cytogenetic events, the updated guidelines 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 variants [2] and uncouples the classification of a CNV’s pathogenicity from its implications for any particular individual.

The process of classifying a CNV that impacts a single gene in accordance with these guidelines involves answering 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 guidelines 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. For duplications of triplosensitive genes, this process simply involves verifying that the entire coding region of the gene is duplicated. However, for intragenic CNVs within established haploinsufficient genes, the process is more complicated and involves many different considerations, 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

Section 2 of the new CNV guidelines describes the process for scoring a CNV based on its impact on the gene.


  1. 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.
  2. 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.