Journal article
Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss
Genetics in medicine, Vol.23(11), pp.2208-2212
11/2021
DOI: 10.1038/s41436-021-01254-2
PMCID: PMC8556313
PMID: 34230634
Abstract
The ClinGen Variant Curation Expert Panels (VCEPs) provide disease-specific rules for accurate variant interpretation. Using the hearing loss-specific American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, the Hearing Loss VCEP (HL VCEP) illustrates the utility of expert specifications in variant interpretation.
A total of 157 variants across nine HL genes, previously submitted to ClinVar, were curated by the HL VCEP. The curation process involved collecting published and unpublished data for each variant by biocurators, followed by bimonthly meetings of an expert curation subgroup that reviewed all evidence and applied the HL-specific ACMG/AMP guidelines to reach a final classification.
Before expert curation, 75% (117/157) of variants had single or multiple variants of uncertain significance (VUS) submissions (17/157) or had conflicting interpretations in ClinVar (100/157). After applying the HL-specific ACMG/AMP guidelines, 24% (4/17) of VUS and 69% (69/100) of discordant variants were resolved into benign (B), likely benign (LB), likely pathogenic (LP), or pathogenic (P). Overall, 70% (109/157) variants had unambiguous classifications (B, LB, LP, P). We quantify the contribution of the HL-specified ACMG/AMP codes to variant classification.
Expert specification and application of the HL-specific ACMG/AMP guidelines effectively resolved discordant interpretations in ClinVar. This study highlights the utility of ClinGen VCEPs in supporting more consistent clinical variant interpretation.
Details
- Title: Subtitle
- Disease-specific ACMG/AMP guidelines improve sequence variant interpretation for hearing loss
- Creators
- Mayher J Patel - Broad InstituteMarina T DiStefano - Broad InstituteAndrea M Oza - Boston Children's HospitalMadeline Y Hughes - Broad InstituteEmma H Wilcox - Broad InstituteSarah E Hemphill - Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, USABrandon J Cushman - Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge, USAAndrew R Grant - Broad InstituteRebecca K Siegert - Broad InstituteJun Shen - Harvard UniversityAlex Chapin - ARUP LaboratoriesNicole J Boczek - Mayo ClinicLisa A Schimmenti - Mayo ClinicKiyomitsu Nara - National Hospital OrganizationMargaret Kenna - Boston Children's HospitalHela Azaiez - University of IowaKevin T Booth - University of IowaKaren B Avraham - Tel Aviv UniversityHannie Kremer - Radboud University NijmegenAndrew J Griffith - University of Tennessee Health Science CenterHeidi L Rehm - Broad InstituteSami S Amr - Harvard UniversityAhmad N Abou Tayoun - University of Medicine and Health SciencesClinGen Hearing Loss Clinical Domain Working Group
- Contributors
- Richard Smith (Contributor) - University of Iowa, Otolaryngology
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.23(11), pp.2208-2212
- DOI
- 10.1038/s41436-021-01254-2
- PMID
- 34230634
- PMCID
- PMC8556313
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Grant note
- U24 HG006834 / NHGRI NIH HHS U41 HG006834 / NHGRI NIH HHS
- Language
- English
- Date published
- 11/2021
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256932902771
Metrics
31 Record Views