In the webcast, Evaluation of Copy Number Variants with VSClinical’s New ACMG Guideline Workflow, we discussed how VSClinical implements Section 4 of the ACMG guidelines. Specifically, we focused on integrating literature and publications to assess the pathogenicity of a CNV event when there was a lack of dosage sensitivity information.

One of the primary pieces of evidence for evaluating genes that lack dosage sensitivity information is the phenotype specificity. This is important because it is easier to identify pathogenic events if the associated phenotype is highly specific in relation to a small set of genes. To illustrate this example, we used a CNV deletion that spanned 10 genes and was associated with Brachydactyly type E (BDE), an isolated form of Brachydactyly. In VSClinical, we showed how a user could enter a phenotypic term such as BDE, and the algorithm would rank each gene and identify those that should be used for further evaluation.

For those who were unable to join us for our recent webcast, we have a recording below of our navigation of evaluating copy number variants with VSClinical’s new ACMG guideline workflow.

The next step was a literature search for similar CNV events or loss of function variants that occurred in the same gene. The ideal literature is composed of a couple different components. This includes case-level/case-control data, phenotype, inheritance, and segregation. In the webcast, we used this as criteria to identify publications associated with different structures of inheritance and then transitioned into VSClinical.

The information from the available literature was entered into VSClinical using intuitive decision trees. Ultimately, this allowed us to combine the total scores for the different publications and develop a final classification. All information was then saved to the assessment catalog and rendered into a clinical report.

Together, this webcast showed how Section 4 is implemented into VSClinical and how this automation alleviates the complexities of the new ACMG CNV Guidelines. If you have not seen this webcast or others similar, I would highly encourage you to check them out on our webcast page. Or feel free to check out some of our other blogs that always contains important news and updates.