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

TLDR

Hearing loss is genetically heterogeneous, so clinical testing sequences many genes and yields numerous novel variants, making standardization of variant interpretation essential for consistent and accurate diagnoses. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP hearing‑loss rules. The Hearing Loss Variant Curation Expert Panel, established within the Clinical Genome Resource, adapted ACMG/AMP guidelines for hearing‑loss genes and validated the resulting rules with a pilot set of 51 variants assessed by curators and disease experts. Three rules remained unchanged, four were removed, and 21 were specified; in the pilot, 37 % (19/51) of variants changed category when applying the expert panel rules, demonstrating that HL‑specific ACMG/AMP rules will help standardize interpretation and improve patient care.

Abstract

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.