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

Shen, J.; Oza, A.; del Castillo, I.; Duzkale, H.; Matsunaga, T.; Pandya, A.; Kang, H.; Mar-Heyming, R.; Guha, S.; Moyer, K.; Lo, C.; Kenna, M.; Alexander, J.; Zhang, Y.; Hirsch, Y.; Luo, M.; Cao, Y.; Wai Choy, K.; Cheng, Y.-F.; Avraham, K.; Hu, X.; Garrido, G.; Moreno-Pelayo, M.; Greinwald, J.; Zhang, K.; Zeng, Y.; Brownstein, Z.; Basel-Vanagaite, L.; Davidov, B.; Frydman, M.; Weiden, T.; Nagan, N.; Willis, A.; Hemphill, S.; Grant, A.; Siegert, R.; DiStefano, M.; Amr, S.; Rehm, H.; Abou Tayoun, A.; The ClinGen Hearing Loss Working Group,

doi:10.1101/493130

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bioRxiv · 10.1101/493130

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

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Abstract

PURPOSEPathogenic 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of these two variants.\n\nMETHODSThe ClinGen Hearing Loss Expert Panel (HL-EP) collected published data and shared unpublished information from participating laboratories regarding the two variants. Functional, computational, allelic, and segregation data were also obtained.\n\nRESULTSThe panel reviewed the synthesized information, and classified the Met34Thr and Val37Ile variants according to professional variant interpretation guidelines. We found that Met34Thr and Val37Ile are significantly overrepresented in hearing loss patients, compared to the general population. Met34Thr or Val37Ile homozygotes or compound heterozygotes typically manifest mild to moderate hearing loss. Several other types of evidence also support pathogenic roles for those two variants.\n\nCONCLUSIONResolving controversies in variant classification requires coordinated effort among a panel of international multi-institutional experts to share data, standardize classification rules, review evidence, and reach a consensus. The ClinGen HL-EP concluded that Met34Thr and Val37Ile variants in GJB2 are pathogenic for autosomal recessive nonsyndromic hearing loss with variable expressivity and age-dependent penetrance.

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Shen, J., Oza, A., del Castillo, I., Duzkale, H., Matsunaga, T., Pandya, A., Kang, H., Mar-Heyming, R., Guha, S., Moyer, K., Lo, C., Kenna, M., Alexander, J., Zhang, Y., Hirsch, Y., Luo, M., Cao, Y., Wai Choy, K., Cheng, Y.-F., Avraham, K., Hu, X., Garrido, G., Moreno-Pelayo, M., Greinwald, J., Zhang, K., Zeng, Y., Brownstein, Z., Basel-Vanagaite, L., Davidov, B., Frydman, M., Weiden, T., Nagan, N., Willis, A., Hemphill, S., Grant, A., Siegert, R., DiStefano, M., Amr, S., Rehm, H., Abou Tayoun, A., The ClinGen Hearing Loss Working Group,. 2018-12-11. Consensus interpretation of the Met34Thr and Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel. https://doi.org/10.1101/493130

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