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Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

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

Author information

1
Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.
2
Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts.
3
Harvard Medical School, Boston, Massachusetts.
4
Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts.
5
ARUP Laboratories, Salt Lake City, Utah.
6
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
7
Department of Otorhinolaryngology, Clinical Genomics and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
8
Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
9
Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and Clinics, Iowa City, Iowa.
10
The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa.
11
Audiology Unit, National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, Maryland.
12
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
13
Department of Otorhinolaryngology and Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
14
Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts.
15
The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
16
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
17
The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

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

PMID:
30311386
PMCID:
PMC6188673
[Available on 2019-11-01]
DOI:
10.1002/humu.23630

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