15. SMAD4 p.I500V Studies and Clinical SectionΒΆ

The Studies tab of VSClinical allows users to search for relevant literature regarding the variant. Specifically, in the Clinical and Functional Studies section, this variant can be searched in Google, Google Scholar or PubMed from their corresponding links. Additionally, the detailed assessments and citations of labs submitting this variant to ClinVar can be reviewed. There are 14 ClinVar assessments for this variant, which show the source of interpretation, the guidelines used and a summary that can be added to the evaluation. As an example, add the interpretation from GeneDx into the Summary section of Clinical and Functional Studies by copy and pasting, or by hovering over the blue plus icon and selecting Add Text to My Clinical Summary. Next, under Reported Variant(s) Amino Acid Change, select Same Change (I500V) and Same Residue I500. Under the Observed State and Number of Probands, select de Novo. Then under the Disorder or Clinical Description, select Myhre Syndrome. With the available literature being referenced, you can then answer Yes to both PS1 and PM5, which brings the final predicted classification to Pathogenic. After answering these criteria, click on the Clinical tab, to investigate the last criteria.

Clinical studies tab.

Figure 15-1: Clinical studies tab for literature referencing.

In the Clinical section there are scoring criteria that can be applied when there is known family history of the disorder. For this patient, we know that the variant of interest is a de novo variant but we do not have evidence that both parental samples, through identity testing, are the biological parents. Even though the parents have not been tested to be the biological parents, we have the option to assume that they are. With this eveidence, we will answer Yes to De novo variant and the patient has the disorder but no family history and Unconfirmed (Asumed) to Maternity and paternity confirmed, which applies the scoring criteria PM6. Since we have now answered all relevant criteria, let’s go back to the main Classificaiton tab.

Clinical studies tab.

Figure 15-2: Applying PM6 in the Clinical tab.

At this point all of the criteria have been accounted for, the interpretation built and the final classification presented, which is Pathogenic following rule iii of the ACMG guidelines: 1 strong, AND 3 moderate and 2 supporting criteria.

The ACMG Classification Summary Panel.

Figure 15-3: The ACMG Classification Summary Panel.

In summary, this has been determined to be a straight-forward Pathogenic variant, so we want to include this in the final report, and specifically in the primary findings. To do this, scroll to the Interpretation section at the bottom of the Classification tab. Under the Interpretation section, select the Primary Findings check box and verify that Pathogenic is selected in the Classification drop-down menu. In the For Disorder: box, selecting the option will provide a list of associated phenotypes based on the OMIM annotation source. Select Myhre Syndrome, and we will leave the Inheritance/Variant Type as default. Lastly, we will add the interpretation created from the evaluation using the Auto Interpretation on the right side. From the Auto Interpretation scroll down and select Add to Interpretation, which will populate in the Interpretation section.

Filling in the Interpretation Section.

Figure 15-4: Populating the variant interpretation.

Once the information has been filled in, the variant interpretation can be saved by selecting Save>Save & Finalize Samples>Finalize. If there were other variants pulled into the evaluation, the user could select Save and Next Variant to complete the evaluation and interpretation process for the other variants. However, for this project we will now demonstrate how to render a clinical report using our saved variant interpretation.