Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel

• Type of Material: Article
• Authors: Jun Shen, Harvard Medical School; Andrea M. Oza, Harvard Medical School; Ignacio del Castillo, Hospital Universitario Ramon y Cajal; Hatice Duzkale, Cincinnati Childrens Hospital Medical Center; Tatsuo Matsunaga, National Hospital Organization Tokyo Medical Center; Arti Pandya, University of North Carolina; Hyunseok P. Kang, Counsyl; Rebecca Mar-Heyming, Counsyl; Saurav Guha, Counsyl; Krista Moyer, Counsyl; Christine Lo, Counsyl; Margaret Kenna, Harvard Medical School; John Alexander, Emory University; Yan Zhang, Guangdong Women & Childrens Hospital; Yoel Hirsch, Committee for Prevention of Jewish Genetic Diseases; Minjie Luo, Childrens Hospital of Philadelphia; Ye Cao, Chinese University of Hong Kong; Kwong Wai Choy, Chinese University of Hong Kong; Yen-Fu Cheng, Taipei Veterans General Hospital; Karen B. Avraham, Tel Aviv University; Xinhua Hu, Indiana University; Gema Garrido, Hospital Universitario Ramon y Cajal; Miguel A. Moreno-Pelayo, Hospital Universitario Ramon y Cajal; John Greinwald, Cincinnati Childrens Hospital Medical Center; Kejian Zhang, Cincinnati Childrens Hospital Medical Center; Yukun Zeng, Guangdong Women & Childrens Hospital; Zippora Brownstein, Tel Aviv University; Lina Basel-Salmon, Tel Aviv University; Bella Davidov, Tel Aviv University; Moshe Frydman, Tel Aviv University; Tzvi Weiden, Committee for Prevention of Jewish Genetic Diseases; Narasimhan Nagan, Laboratory Corporation of America® Holdings; Alecia Willis, Laboratory Corporation of America® Holdings; Sarah E. Hemphill, Partners HealthCare Personalized Medicine; Andrew R. Grant, Partners HealthCare Personalized Medicine; Rebecca K. Siegert, Partners HealthCare Personalized Medicine; Marina T. DiStefano, Partners HealthCare Personalized Medicine; Sami S. Amr, Harvard Medical School; Heidi L. Rehm, Harvard Medical School; Ahmad N. Abou Tayoun, Al Jalila Childrens Specialty Hospital
• Language: English
• Date: 2019-11-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41436-019-0535-9
• Title of Journal or Parent Work: Genetics in Medicine
• Volume: 21
• Issue: 11
• Start Page: 2442
• End Page: 2452
• Grant/Funding Information: This work was supported by NIH/NIDCD grants R03DC013866 and R01DC015052 (to JS), R01DC011835 (to KBA), NIH/NINDS R01AR059049, NIH/NHGRI U01HG008666 and three other intramural grants (to KZ), a Grant-in-Aid for Clinical Research from the National Hospital Organization H27-NHOkankaku-02, Japan (to TM), Spanish Instituto de Salud Carlos III grants PI14/01162 (to IC) and PI14/0948 (to MAM-P), Regional Government of Madrid-Spain RAREGENOMICS-CAM grant B2017/BMD3721 (to MAM-P), and Plan Estatal de I+D+I 2013–2016 with co-funding from the European Regional Development Fund (to IC and MAM-P).
• Keywords: Frequency; Life Sciences & Biomedicine; M34T mutation; variant classification; incomplete penetrance; Genetics & Heredity; Genotype; Deafness; Channel; Connexin 26 gene; Phenotype; Science & Technology; variant interpretation; Guidelines; Identification; Impairment; hearing loss; ClinGen
• Research Categories: Health Sciences, Pathology; Biology, Genetics; Health Sciences, Opthamology

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.