For informational purposes only.
We believe these sources to be reliable and accurate, but the information herein cannot be construed as diagnositic.
What is a VUS?
That means there is not yet enough information to classify the gene variant as benign or pathogenic.1
How do I interpret a VUS?
For a step-by-step guide on how to analyze a sample VUS report from Invitae’s primary immunodeficiency panel, watch the video below. Dr Jolan Walter, Division Chief of Pediatric Allergy & Immunology at University of South Florida and Johns Hopkins All Children’s Hospital, walks through an example report line-by-line and provides information for how to get further assistance.
Learn more about a VUS in PIK3CD or PIK3R1
Pharming Medical Affairs representatives are available to discuss what resources are available to help you interpret a VUS. Please fill out the form with your preferred contact information and any details pertinent to your request.
Additional resources for assessing pathogenicity
Several manuscripts provide education and guidance on interpreting a VUS. Some of these also walk through examples.
Chinn IK, Chan AY, Chen K, et al. Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2020;145(1):46-69.
- Review the supplementary data for a checklist of criteria to assess when interpreting a VUS
- This article also includes a list of useful databases/resources that are helpful for gathering evidence
Sullivan KE. The scary world of variants of uncertain significance (VUS): A hitchhiker’s guide to interpretation. J Allergy Clin Immunol. 2021;147(2):492-494.
- This article presents several simplified workflows for interpreting a VUS for autosomal dominant and autosomal recessive conditions, using severe combined immunodeficiency (SCID) as an example disease
Thauland TJ, Pellerin L, Ohgami RS, Bacchetta R, Butte MJ. Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome. Front Immunol. 2019;10:753.
- An APDS case study in which the authors determine the pathogenicity of a PIK3CD VUS
Databases and listservs
Information about VUSs and connections to experts may help you interpret a VUS.
ClinVar: National Institutes of Health (NIH)-funded archival database of genomic variation and its relationship to human health. This database is driven by submissions from researchers, testing labs, expert panels, and others. ClinVar then standardizes the descriptions of the variants, conditions, and terms of clinical significance.2,3
ClinGen: NIH-funded central resource that defines the clinical relevance of genes and variants. Rather than relying on submissions, ClinGen uses panels of experts to curate gene and variant information, with the aim of improving patient care.3 ClinGen is in the process of adding APDS variants to their database.4 Please check the site for the latest information on curated variants in PIK3CD and PIK3R1.
VUSserve: CIS-run listserv containing information about VUS in immunologically relevant genes, and connecting healthcare professionals who have identified a VUS with experts who may be able to assist with determining whether benign or pathogenic.5
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- Richards S, et al. Genet Med. 2015;17(5):405-424.
- National Center for Biotechnology Information (NCBI). ClinVar website. https://www.ncbi.nlm.nih.gov/clinvar/. Accessed September 2, 2021.
- ClinGen website. https://clinicalgenome.org/. Accessed September 2, 2021.
- Clinical Domain Working Groups: Antibody Deficiencies Variant Curation Expert Panel. ClinGen website. https://clinicalgenome.org/affiliation/50095/. Accessed August 31, 2021.
- Clinical Immunology Society. Listserv website. https://clinimmsoc.org/CIS/News/Listserv.htm. Accessed September 2, 2021.