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 Methods: The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants.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 language | English (US) |
|---|---|
| Journal | Genetics in Medicine |
| DOIs | |
| State | Accepted/In press - Jan 1 2019 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel
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
Y1 - 2019/1/1
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.
KW - ClinGen
KW - hearing loss
KW - incomplete penetrance
KW - variant classification
KW - variant interpretation
UR - http://www.scopus.com/inward/record.url?scp=85067004648&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067004648&partnerID=8YFLogxK
U2 - 10.1038/s41436-019-0535-9
DO - 10.1038/s41436-019-0535-9
M3 - Article
C2 - 31160754
AN - SCOPUS:85067004648
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
ER -