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

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...

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Bibliographic Details
Published inHuman mutation Vol. 39; no. 11; pp. 1593 - 1613
Main Authors Oza, Andrea M., DiStefano, Marina T., Hemphill, Sarah E., Cushman, Brandon J., Grant, Andrew R., Siegert, Rebecca K., Shen, Jun, Chapin, Alex, Boczek, Nicole J., Schimmenti, Lisa A., Murry, Jaclyn B., Hasadsri, Linda, Nara, Kiyomitsu, Kenna, Margaret, Booth, Kevin T., Azaiez, Hela, Griffith, Andrew, Avraham, Karen B., Kremer, Hannie, Rehm, Heidi L., Amr, Sami S., Abou Tayoun, Ahmad N.
Format Journal Article
LanguageEnglish
Published United States Hindawi Limited 01.11.2018
Subjects
ACMG/AMP guidelines
ClinGen
deafness
Gene Frequency - genetics
genetic diagnosis
Genetic Testing - methods
Genetic Variation - genetics
Genome, Human - genetics
Genomics
Genomics - methods
Hearing loss
Hearing Loss - genetics
Humans
Mutation - genetics
Sequence Analysis, DNA
Societies, Medical
Standardization
United States
variant interpretation
United States
ACMG/AMP guidelines
genetic diagnosis
hearing loss
deafness
ClinGen
variant interpretation
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Summary: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. The Hearing Loss Variant Curation Expert panel was created within ClinGen with the goals of standardizing variant interpretation in hearing loss, resolving existing discrepancies in submitted variant classifications in ClinVar and providing expert variant classifications for hearing loss. Here we present specifications of the ACMG/AMP variant interpretation guidelines for hearing loss and the results of a pilot project in which these specifications were applied to 51 variants in the CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA, and USH2A genes.
Bibliography:Funding information
Research reported in this publication was supported by the National Human Genome Research Institute (NHGRI) under award number U41HG006834. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.
For the ClinGen/ClinVar Special Issue
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Authorship Contributions
The work was overseen by the three co-chairs of the HL-EP: HLR, SSA and ANAT. AMO served as the coordinator for the HL-EP. The iterative ACMG/AMP rule specifications for discussion with the working group were developed and prepared by AMO, SEH, BJC, ARG, MTD, and RKS. AMO and ANAT created the first draft of the manuscript and SEH, ARG, MTD, RKS, LAS, KTB, HA, KBA, MK, HLR, Yu Lu, Hatice Duzkale, Ignacio del Castillo, Minjie Luo, Xue Liu, Huijun Yuan, and Wenying Zhang provided critical edits and feedback. The final version was approved by all authors.
The following authors performed primary variant curations for the variant pilot: AMO, SEH, BJC, ARG, MTD, RKS, AC, NJB, LAS, JM, LH, KN, and JS. AG contributed to rules that impacted SLC26A4, including population based rules (BA1, BS1, PM2), functional evidence rules (PS3, BS3), and phenotype-specific rules (PP4). HK helped develop the population based rules (BA1, BS1, PM2) and the phenotype-specific rules (PP4). KTB, HA, and KBA shared internal laboratory data that were instrumental in the development of the population data based rules and classification of pilot variants. MK and LAS provided their expert clinical knowledge.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.23630