VUS Resources

For informational purposes only.

We believe these sources to be reliable and accurate, but the information herein cannot be construed as diagnostic.

What is a variant of uncertain significance (VUS)?

An indication of a VUS means that there is not enough information to classify the gene variant as benign or pathogenic.1

Why are variants of uncertain significance (VUSs) important to understand?

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions.2
  • That being said, VUSs can be easily misinterpreted by healthcare providers and families
  • VUSs differ greatly in their likelihood of being pathogenic
  • The classification of a VUS can change over time
  • Testing parents may help with the interpretation
  • And lastly, VUSs should not be used to inform clinical management decision-making3
Dr. Jolan Walter is the division chief of Pediatric Allergy and Immunology at Johns Hopkins All Children’s Hospital and a professor at the University of South Florida. In this video, she describes how to analyze VUS genetic test results and walks through a sample report analysis.
Analyzing A Variant of Uncertain Significance (VUS)

Learn more about a VUS in PIK3CD or PIK3R1

To learn about additional resources to help you interpret a VUS, please contact Pharming Medical Information at pharmingcanadamc@eversana.com

Additional resources for assessing pathogenicity

References

Several manuscripts provide education and guidance on interpreting a VUS. Some of these also walk through examples. Chinn IK, 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, et al. 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.4

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.5 ClinGen is in the process of adding APDS variants to their database.6 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.7

Refer your patient to an APDS Physician

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References:

1. Richards S, 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. Genet Med. 2015;17(5):405–424. 2. Chinn IK, 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. 3. Joynt ACM, et al. Understanding genetic variants of uncertain significance. Paediatr Child Health. 2021;27(1):10–11. 4. National Center for Biotechnology Information (NCBI). ClinVar website. Available at: https://www.ncbi.nlm.nih.gov/clinvar/. Accessed March 7, 2024. 5. ClinGen website. Available at: https://clinicalgenome.org/. Accessed March 7, 2024. 6. ClinGen website. Clinical Domain Working Groups: Antibody deficiencies variant curation expert panel. Available at: https://clinicalgenome.org/affiliation/50095/. Accessed March 7, 2024. 7. Clinical Immunology Society. Listserv website. Available at: https://clinimmsoc.org/CIS/News/Listserv.htm. Accessed March 7, 2024.
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