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

on behalf of the ClinGen Hearing Loss Working Group

Research output: Contribution to journalArticle

1 Citation (Scopus)

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 Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants.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.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StateAccepted/In press - Jan 1 2019
Externally publishedYes

Fingerprint

Hearing Loss
Consensus
Guidelines
Population Control
Penetrance
Sensorineural Hearing Loss

Keywords

  • ClinGen
  • hearing loss
  • incomplete penetrance
  • variant classification
  • variant interpretation

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. / on behalf of the ClinGen Hearing Loss Working Group.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

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title = "Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel",
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",
author = "{on behalf of the ClinGen Hearing Loss Working Group} and Jun Shen and Oza, {Andrea M.} and {del Castillo}, Ignacio and Hatice Duzkale and Tatsuo Matsunaga and Arti Pandya and Kang, {Hyunseok P.} and Rebecca Mar-Heyming and Saurav Guha and Krista Moyer and Christine Lo and Margaret Kenna and Alexander, {John J.} and Yan Zhang and Yoel Hirsch and Minjie Luo and Ye Cao and {Wai Choy}, Kwong and Cheng, {Yen Fu} and Avraham, {Karen B.} and Xinhua Hu and Gema Garrido and Moreno-Pelayo, {Miguel A.} and John Greinwald and Kejian Zhang and Yukun Zeng and Zippora Brownstein and Lina Basel-Salmon and Bella Davidov and Moshe Frydman and Tzvi Weiden and Narasimhan Nagan and Alecia Willis and Hemphill, {Sarah E.} and Grant, {Andrew R.} and Siegert, {Rebecca K.} and DiStefano, {Marina T.} and Amr, {Sami S.} and Rehm, {Heidi L.} and {Abou Tayoun}, {Ahmad N.} and Hela Azaiez and Booth, {Kevin T.} and Smith, {Richard J.} and Giersch, {Anne B.} and Morton, {Cynthia C.} and Liu, {Xue Z.} and Mustafa Tekin and Yu Lu and Huijun Yuan and Hideki Mutai",
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AU - on behalf of the ClinGen Hearing Loss Working Group

AU - Shen, Jun

AU - Oza, Andrea M.

AU - del Castillo, Ignacio

AU - Duzkale, Hatice

AU - Matsunaga, Tatsuo

AU - Pandya, Arti

AU - Kang, Hyunseok P.

AU - Mar-Heyming, Rebecca

AU - Guha, Saurav

AU - Moyer, Krista

AU - Lo, Christine

AU - Kenna, Margaret

AU - Alexander, John J.

AU - Zhang, Yan

AU - Hirsch, Yoel

AU - Luo, Minjie

AU - Cao, Ye

AU - Wai Choy, Kwong

AU - Cheng, Yen Fu

AU - Avraham, Karen B.

AU - Hu, Xinhua

AU - Garrido, Gema

AU - Moreno-Pelayo, Miguel A.

AU - Greinwald, John

AU - Zhang, Kejian

AU - Zeng, Yukun

AU - Brownstein, Zippora

AU - Basel-Salmon, Lina

AU - Davidov, Bella

AU - Frydman, Moshe

AU - Weiden, Tzvi

AU - Nagan, Narasimhan

AU - Willis, Alecia

AU - Hemphill, Sarah E.

AU - Grant, Andrew R.

AU - Siegert, Rebecca K.

AU - DiStefano, Marina T.

AU - Amr, Sami S.

AU - Rehm, Heidi L.

AU - Abou Tayoun, Ahmad N.

AU - Azaiez, Hela

AU - Booth, Kevin T.

AU - Smith, Richard J.

AU - Giersch, Anne B.

AU - Morton, Cynthia C.

AU - Liu, Xue Z.

AU - Tekin, Mustafa

AU - Lu, Yu

AU - Yuan, Huijun

AU - Mutai, Hideki

PY - 2019/1/1

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N2 - 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.

AB - 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.

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KW - hearing loss

KW - incomplete penetrance

KW - variant classification

KW - variant interpretation

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