VUS: Variant of uncertain significance or very unclear situation?

Stephan Kemp, Joseph J. Orsini, Merel S. Ebberink, Marc Engelen, Troy C. Lund

Research output: Contribution to journalComment/debatepeer-review

3 Scopus citations


The advancements in population screening, including newborn screening, enables the identification of disease-causing variants and timely initiation of treatment. However, screening may also identify mild variants, non-disease variants, and variants of uncertain significance (VUS). The identification of a VUS poses a challenge in terms of diagnostic uncertainty and confusion. X-linked adrenoleukodystrophy (ALD) serves as an illustrative example of this complex issue. ALD is a monogenic neurometabolic disease with a complex clinical presentation and a lack of predictive tests for clinical severity. Despite the success of ALD newborn screening, a significant proportion (62%) of missense variants identified through newborn screening exhibit uncertainty regarding their pathogenicity. Resolving this issue requires ongoing efforts to accurately classify variants and refine screening protocols. While it is undisputable that ALD newborn screening greatly benefits boys with the disease, the identification of VUS underscores the need for continuous research and collaboration in improving screening practices.

Original languageEnglish (US)
Article number107678
JournalMolecular Genetics and Metabolism
Issue number1-2
StatePublished - Sep 1 2023

Bibliographical note

Publisher Copyright:
© 2023


  • Adrenoleukodystrophy
  • Diagnostic uncertainty
  • Newborn screening
  • Population screening
  • Variant of uncertain significance (VUS)

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't


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