Webcast Recap: A User’s Perspective: ACMG Guidelines for CNVs in VSClinical

         October 16, 2020

Our previous webcast from VP Gabe Rudy in September exposed us to some fundamentals of this years’ updated 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). This recent webcast was dedicated to breaking down these new guidelines with examples to help familiarize our users and audience on how to apply the criteria and build CNV classifications in VarSeq.

In our User’s Perspective webcast, our Director of Research, Ph.D. Nathan Fortier provides a history of our front-line efforts to implement these new guidelines and gives a breakdown of their application logic. There was a huge developmental effort spanning the last year to get these guidelines implemented. There was an early collaboration to gain insight from the ClinGen group directly (big thanks to Erin Riggs!) and this developmental focus will be maintained as new standards/guidelines are developed in the future.

For those who were unable to join us for our recent webcast, we have a recording link below of our navigation through the latest features in VSClinical CNV ACMG Guidelines.

Additionally, I then demonstrated this guideline process in the VarSeq software. Users now will be able to leverage a CNV ACMG classification filter criteria to optimize their tertiary analysis and narrow the search to clinically relevant CNVs even faster. The first of two examples was an obvious pathogenic heterozygous deletion in exon 23 of BRCA1 due to the association of strong haploinsufficiency recorded in ClinGen. The ACMG CNV classifier itself handles the majority of classification work, automating much of the 80+ criteria processed in CNV evaluation. The second example demonstrated VarSeq’s new trio CNV analysis capability and showcased a heterozygous deletion event of uncertain significance in exons 4-6 of the DSG2 gene. The consideration with the second example is that there was little evidence for dosage sensitivity from ClinGen, so the user would then seek to compile their own dosage sensitivity record by capturing affected samples sharing similar events in relevant genes.

Here are some of the great questions asked during the webcast:

Q: Is the ACMG Sample Classifier a separate license feature from the CNV caller?

A: The new CNV features will be available with the combination of VSClinical and CNV calling. Please reach out to our area directors if you wish to know more details on pricing.

Q: Are there any future changes to the ACMG CNV guidelines that you are aware of?


A: Currently we have not received and new information from ClinGen, but we are taking the forefront in this as we are in close contact with customers in the US and internationally that are testing the CNV guidelines and giving us their feedback. That information is then being communicated with ClinGen and helping them build and improve the guidelines.

Q: In the case of CNVs there are additional rules implemented for the ACMG Guidelines formulated by the Ellard group (such as updates to PVS1). Has this been reviewed by Golden Helix?

A: We are aware of the revisions provided by the Ellard group regarding PVS1 and this has been integrated into the ACMG guidelines. This is undergoing testing internally and with our customers. Once completed we will cover it in a different webcast.

Q: When is this feature going to be released?

A: Planned to release early November. Sign up for our marketing newsletter to be the first to know when this is available here.

The goal of this webcast was to not only showcase the new powerful features in VarSeq but also expose users to the process to simplify their usage when they get their hands on the software. However, we do realize this process is sophisticated and if you seek guidance I would encourage you to reach out to our support team for a one-on-one training call. Also, many of you may seek to run some CNV validation data while transitioning to next-gen sequencing detection strategies. I’d recommend starting with some of the recent publications our users have created on their validation results against traditional methods.

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