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

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.

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

Figure 1.

Population data criteria for autosomal recessive and autosomal dominant hearing loss. Minor allele frequencies are represented in decimals above each bar. Abbreviations:PM2_P = PM2_Supporting, BS1_P = BS1_Supporting.

Figure 2.

Distribution of pilot variants (n=51) by gene.

Figure 3.. Frequency of rules applied during the pilot.

The frequency with which ACMG/AMP rules were applied during the variant pilot and the final classification of the variant when the rule was applied. Rules applied with a modified strength are denoted by the rule followed by _P for Supporting, _M for Moderate, _S for Strong, and _VS for Very Strong.

Figure 4.. Final variant classifications of 51 pilot variants compared to initial classifications in ClinVar.

The total height of each bar represents the total number of variants that were given each classification the HL-EP. The colored segments of each bar represent variants whose ClinVar classification differed from the HL-EP classification. Codes listed in the colored segments of the bars indicate the criteria used to classify the variants that changed category during the variant pilot. Codes were only listed once if they were used for multiple variants in the same category.