The role of clinical response to treatment in determining pathogenicity of genomic variants

Genet Med. 2021 Mar;23(3):581-585. doi: 10.1038/s41436-020-00996-9. Epub 2020 Oct 22.


Purpose: The 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants provide a framework to standardize terminology in the classification of variants uncovered through genetic testing. We aimed to assess the validity of utilizing clinical response to therapies specifically targeted to a suspected disease in clarifying variant pathogenicity.

Methods: Five families with disparate clinical presentations and different genetic diseases evaluated and treated in multiple diagnostic settings are summarized.

Results: Extended evaluations indicated possible genetic diagnoses and assigned candidate causal variants, but the cumulative clinical, biochemical, and molecular information in each instance was not completely consistent with the identified disease. Initiation of treatment specific to the suspected diagnoses in the affected individuals led to clinical improvement in all five families.

Conclusion: We propose that the effect of therapies that are specific and targeted to treatable genetic diseases embodies an in vivo physiological response and could be considered as additional criteria within the 2015 ACMG/AMP guidelines in determining genomic variant pathogenicity.

Keywords: 2015 ACMG/AMP guidelines; clinical genetic testing; interpretation; treatable human conditions; variant classification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Genetic Testing
  • Genetic Variation*
  • Genome, Human* / genetics
  • Genomics
  • Humans
  • Sequence Analysis, DNA
  • Virulence