Journal article
Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel
Genetics in medicine, Vol.21(11), pp.2442-2452
11/2019
DOI: 10.1038/s41436-019-0535-9
PMCID: PMC7235630
PMID: 31160754
Abstract
Pathogenic variants in GJB2 are the most common cause of autosomal recessive sensorineural hearing loss. The classification of c.101T>C/p.Met34Thr and c.109G>A/p.Val37Ile in GJB2 are controversial. Therefore, an expert consensus is required for the interpretation of these two variants.
The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants. Functional, computational, allelic, and segregation data were also obtained. Case-control statistical analyses were performed.
The panel reviewed the synthesized information, and classified the p.Met34Thr and p.Val37Ile variants utilizing professional variant interpretation guidelines and professional judgment. We found that p.Met34Thr and p.Val37Ile are significantly overrepresented in hearing loss patients, compared with population controls. Individuals homozygous or compound heterozygous for p.Met34Thr or p.Val37Ile typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for these two variants.
Resolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification guidelines, review evidence, and reach a consensus. We concluded that p.Met34Thr and p.Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and incomplete penetrance.
Details
- Title: Subtitle
- Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel
- Creators
- Jun Shen - Harvard UniversityAndrea M Oza - Boston Children's HospitalIgnacio Del Castillo - Centre for Biomedical Network Research on Rare DiseasesHatice Duzkale - Cincinnati Children's Hospital Medical CenterTatsuo Matsunaga - Tokyo Medical CenterArti Pandya - University of North Carolina at Chapel HillHyunseok P Kang - CounsylRebecca Mar-Heyming - CounsylSaurav Guha - New York Genome CenterKrista Moyer - CounsylChristine Lo - CounsylMargaret Kenna - Harvard UniversityJohn J Alexander - Emory UniversityYan Zhang - Guangzhou Women and Children Medical CenterYoel Hirsch - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, USAMinjie Luo - University of PennsylvaniaYe Cao - Chinese University of Hong KongKwong Wai Choy - Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong, ChinaYen-Fu Cheng - National Yang Ming UniversityKaren B Avraham - Rabin Medical CenterXinhua Hu - Indiana University – Purdue University IndianapolisGema Garrido - Instituto Ramón y Cajal de Investigación SanitariaMiguel A Moreno-Pelayo - Instituto Ramón y Cajal de Investigación SanitariaJohn Greinwald - Cincinnati Children's Hospital Medical CenterKejian Zhang - Cincinnati Children's Hospital Medical CenterYukun Zeng - Certer for Medical Genetics, Guangdong Women and Children Hospital, Guangzhou, Guangdong, ChinaZippora Brownstein - Rabin Medical CenterLina Basel-Salmon - Felsenstein Medical Research Center, Petach Tikva, IsraelBella Davidov - Rabin Medical CenterMoshe Frydman - Sheba Medical CenterTzvi Weiden - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, IsraelNarasimhan Nagan - Integrated Genetics, Laboratory Corporation of America® Holdings, Westborough, MA, USAAlecia Willis - Research Triangle Park FoundationSarah E Hemphill - Mass General BrighamAndrew R Grant - Broad InstituteRebecca K Siegert - Broad InstituteMarina T DiStefano - Mass General BrighamSami S Amr - Harvard UniversityHeidi L Rehm - Massachusetts General HospitalAhmad N Abou Tayoun - Al Jalila Children's Specialty Hospital, Dubai, UAE. Ahmad.Tayoun@ajch.aeClinGen Hearing Loss Working GroupRichard J H Smith (Contributor) - University of Iowa, Otolaryngology
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.21(11), pp.2442-2452
- DOI
- 10.1038/s41436-019-0535-9
- PMID
- 31160754
- PMCID
- PMC7235630
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Grant note
- R03 DC013866 / NIDCD NIH HHS R01 AR059049 / NIAMS NIH HHS R01 DC011835 / NIDCD NIH HHS R01 DC015052 / NIDCD NIH HHS L60 MD003721 / NIMHD NIH HHS U01 HG008666 / NHGRI NIH HHS R03DC013866 / NIDCD NIH HHS R01DC011835 / NIDCD NIH HHS R01DC015052 / NIDCD NIH HHS U41 HG006834 / NHGRI NIH HHS
- Language
- English
- Date published
- 11/2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984256838202771
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