Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.


Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL.

Keywords: ACMG/AMP guidelines; ClinGen; deafness; genetic diagnosis; hearing loss; variant interpretation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Gene Frequency / genetics
  • Genetic Testing / methods*
  • Genetic Variation / genetics
  • Genome, Human / genetics*
  • Genomics / methods
  • Hearing Loss / genetics*
  • Humans
  • Mutation / genetics
  • Sequence Analysis, DNA
  • Societies, Medical
  • United States