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

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

  • Genet Med. 2019 Nov;21(11):2442-2452. doi: 10.1038/s41436-019-0535-9.
Jun Shen 1 2 3,  Andrea M Oza 4 5,  Ignacio Del Castillo 6 7,  Hatice Duzkale 8,  Tatsuo Matsunaga 9,  Arti Pandya 10,  Hyunseok P Kang 11,  Rebecca Mar-Heyming 11,  Saurav Guha 11 12,  Krista Moyer 11,  Christine Lo 11,  Margaret Kenna 13 5,  John J Alexander 14 15,  Yan Zhang 16,  Yoel Hirsch 17,  Minjie Luo 18 19,  Ye Cao 20,  Kwong Wai Choy 20,  Yen-Fu Cheng 21 22 23,  Karen B Avraham 24,  Xinhua Hu 25,  Gema Garrido 6 7,  Miguel A Moreno-Pelayo 6 7,  John Greinwald 8,  Kejian Zhang 8,  Yukun Zeng 16,  Zippora Brownstein 24,  Lina Basel-Salmon 24 26 27 28,  Bella Davidov 24,  Moshe Frydman 24 29,  Tzvi Weiden 30,  Narasimhan Nagan 31,  Alecia Willis 32,  Sarah E Hemphill 4,  Andrew R Grant 4 33,  Rebecca K Siegert 4 33,  Marina T DiStefano 4,  Sami S Amr 34 13 4,  Heidi L Rehm 34 13 4 33 35,  Ahmad N Abou Tayoun 36,  ClinGen Hearing Loss Working Group
Affiliations

Affiliations

  • 1 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
  • 2 Harvard Medical School Center for Hereditary Deafness, Boston, MA, USA. [email protected].
  • 3 Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, USA. [email protected].
  • 4 Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, USA.
  • 5 Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 6 Servicio de Genetica, Hospital Universitario Ramon y Cajal, IRYCIS, Madrid, Spain.
  • 7 Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
  • 8 Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
  • 9 Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
  • 10 University of North Carolina, Chapel Hill, NC, USA.
  • 11 Counsyl, South San Francisco, CA, USA.
  • 12 New York Genome Center, New York, NY, 10013, USA.
  • 13 Harvard Medical School Center for Hereditary Deafness, Boston, MA, USA.
  • 14 EGL Genetics/Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
  • 15 ConsulGene, LLC, Jacksonville, FL, USA.
  • 16 Certer for Medical Genetics, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China.
  • 17 Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, USA.
  • 18 The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 19 The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
  • 20 Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong, China.
  • 21 Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan.
  • 22 Department of Otolaryngology-Head and Neck Surgery, Taipei Veterinary Hospital, Taipei, Taiwan.
  • 23 School of Medicine, National Yang-Ming University, Taipei, Taiwan.
  • 24 Raphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
  • 25 Department of Biostatistics, Fairbanks School of Public Health and School of Medicine, Indiana University, Indianapolis, IN, USA.
  • 26 Pediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
  • 27 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 28 Felsenstein Medical Research Center, Petach Tikva, Israel.
  • 29 Danek Gartner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
  • 30 Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, Israel.
  • 31 Integrated Genetics, Laboratory Corporation of America® Holdings, Westborough, MA, USA.
  • 32 Integrated Genetics, Laboratory Corporation of America® Holdings, Research Triangle Park, NC, USA.
  • 33 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 34 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 35 Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 36 Al Jalila Children's Specialty Hospital, Dubai, UAE. [email protected].
PMID: 31160754 DOI: 10.1038/s41436-019-0535-9
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.

Keywords

ClinGen; hearing loss; incomplete penetrance; variant classification; variant interpretation.

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