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

Hum Mutat
Authors
Keywords
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.

Year of Publication
2018
Journal
Hum Mutat
Volume
39
Issue
11
Pages
1593-1613
Date Published
2018 Nov
ISSN
1098-1004
DOI
10.1002/humu.23630
PubMed ID
30311386
PubMed Central ID
PMC6188673
Links
Grant list
U41 HG006834 / HG / NHGRI NIH HHS / United States