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
  • 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.