. 2019 Nov;21(11):2442-2452.

doi: 10.1038/s41436-019-0535-9. Epub 2019 Jun 4.

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

Jun Shen^{1

2

3}, Andrea M Oza^{4

5}, Ignacio Del Castillo^{6

7}, Hatice Duzkale⁸, Tatsuo Matsunaga⁹, Arti Pandya¹⁰, Hyunseok P Kang¹¹, Rebecca Mar-Heyming¹¹, Saurav Guha^{11

12}, Krista Moyer¹¹, Christine Lo¹¹, Margaret Kenna^{13

5}, John J Alexander^{14

15}, Yan Zhang¹⁶, Yoel Hirsch¹⁷, Minjie Luo^{18

19}, Ye Cao²⁰, Kwong Wai Choy²⁰, Yen-Fu Cheng^{21

22

23}, Karen B Avraham²⁴, Xinhua Hu²⁵, Gema Garrido^{6

7}, Miguel A Moreno-Pelayo^{6

7}, John Greinwald⁸, Kejian Zhang⁸, Yukun Zeng¹⁶, Zippora Brownstein²⁴, Lina Basel-Salmon^{24

26

27

28}, Bella Davidov²⁴, Moshe Frydman^{24

29}, Tzvi Weiden³⁰, Narasimhan Nagan³¹, Alecia Willis³², Sarah E Hemphill⁴, Andrew R Grant^{4

33}, Rebecca K Siegert^{4

33}, Marina T DiStefano⁴, Sami S Amr^{34

13

4}, Heidi L Rehm^{34

13

4

33

35}, Ahmad N Abou Tayoun³⁶; ClinGen Hearing Loss Working Group

Collaborators, Affiliations

Collaborators

ClinGen Hearing Loss Working Group:
Hela Azaiez, Kevin T Booth, Richard J Smith, Anne B Giersch, Cynthia C Morton, Xue Z Liu, Mustafa Tekin, Yu Lu, Huijun Yuan, Hideki Mutai, Lisa Schimmenti

Affiliations

¹ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. jshen5@bwh.harvard.edu.
² Harvard Medical School Center for Hereditary Deafness, Boston, MA, USA. jshen5@bwh.harvard.edu.
³ Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, USA. jshen5@bwh.harvard.edu.
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. Ahmad.Tayoun@ajch.ae.

PMID: 31160754
PMCID: PMC7235630
DOI: 10.1038/s41436-019-0535-9

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

Jun Shen et al. Genet Med. 2019 Nov.

. 2019 Nov;21(11):2442-2452.

doi: 10.1038/s41436-019-0535-9. Epub 2019 Jun 4.

Authors

Collaborators

ClinGen Hearing Loss Working Group:
Hela Azaiez, Kevin T Booth, Richard J Smith, Anne B Giersch, Cynthia C Morton, Xue Z Liu, Mustafa Tekin, Yu Lu, Huijun Yuan, Hideki Mutai, Lisa Schimmenti

Affiliations

¹ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. jshen5@bwh.harvard.edu.
² Harvard Medical School Center for Hereditary Deafness, Boston, MA, USA. jshen5@bwh.harvard.edu.
³ Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, USA. jshen5@bwh.harvard.edu.
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. Ahmad.Tayoun@ajch.ae.

PMID: 31160754
PMCID: PMC7235630
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.

PubMed Disclaimer

Conflict of interest statement

Competing Interests Statement

JS, AMO, HD, ML, KZ, SSA, HLR, ANAT worked for pay for service diagnostic laboratories providing genetic testing. PK, SG, BM-H, KM, NN, AW worked for commercial laboratories providing genetic testing.

References

1. Wang NK, Chiang JPW. Increasing evidence of combinatory variant effects calls for revised classification of low-penetrance alleles. Genetics in medicine : official journal of the American College of Medical Genetics. 2018. - PMC - PubMed
1. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine : official journal of the American College of Medical Genetics. 2015;17(5):405–424. - PMC - PubMed
1. Oza AM, DiStefano MT, Hemphill SE, et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Human mutation. 2018;39(11):1593–1613. - PMC - PubMed
1. Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997;387(6628):80–83. - PubMed
1. Scott DA, Kraft ML, Carmi R, et al. Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss. Human mutation. 1998;11(5):387–394. - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous