Systematic evaluation of gene variants linked to hearing loss based on allele frequency threshold and filtering allele frequency

John Hoon Rim, Joon Suk Lee, Jinsei Jung, Ji Hyun Lee, Seung Tae Lee, Jong Rak Choi, Jae Young Choi, Min Goo Lee, Heon Yung Gee

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11 Citations (Scopus)


As the number of genes identified for linkage to hearing loss has been increasing and more public databases have become available, we aimed to systematically evaluate all variants reported for nonsyndromic hearing loss (NSHL) based on their allele frequencies (AFs) in the general population. Among the 3,549 variants in 97 NSHL genes reported as pathogenic/likely pathogenic in ClinVar and HGMD, 1,618 were found in public databases (gnomAD, ExAC, EVS, and 1000G). To evaluate the pathogenicity of these variants, we employed AF thresholds and NSHL-optimized ACMG guidelines. AF thresholds were determined using a high-resolution variant frequency framework and Hardy-Weinberg equilibrium calculation: 0.6% and 0.1% for recessive and dominant genes, respectively. Filtering AFs of variants linked to NSHL were obtained based on AFs reported in gnomAD and ExAC. We found that 48 variants in 23 genes had filtering AFs above the suggested thresholds and assumed that these variants might be benign based on their filtering AFs. 47 variants, except for one notorious high-frequency GJB2 mutation (c.109G > A; p.Val37Ile), were confirmed to be benign/likely benign by the NSHL-optimized ACMG guidelines. The proposed systematic approach will aid in precise evaluation of NSHL variant pathogenicity in the context of filtering AFs, AF thresholds, and NSHL-specific ACMG guidelines, thus improving NSHL diagnostics.

Original languageEnglish
Article number4583
JournalScientific reports
Issue number1
Publication statusPublished - 2019 Dec 1

Bibliographical note

Funding Information:
Bioresources for this study were provided by the National Biobank of Korea, Centers for Disease Control and Prevention, Republic of Korea (4845-301, 4851-302, and 4851-307). This research was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Korea government (MSIT, 2018R1A5A2025079 to H.Y.G).

Publisher Copyright:
© 2019, The Author(s).

All Science Journal Classification (ASJC) codes

  • General


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