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.
The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants.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.
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.
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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We thank members of the ClinGen Hearing Loss Working Group who participated in the discussion on applying ACMG/AMP and HL-specific rules to determine the classification of the p.Met34Thr and p.Val37Ile variants. We thank Donglin Bai of the Schulich School of Medicine & Dentistry, Western University for critical and constructive comments on the manuscript. This work was supported by National Institutes of Health/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD) grants R03DC013866 and R01DC015052 (to J.S.); R01DC011835 (to K.B.A.); NIH/NINDS R01AR059049, NIH/National Human Genome Research Institute (NHGRI) U01HG008666. and three other intramural grants (to K.Z.); a Grant-in-Aid for Clinical Research from the National Hospital Organization H27-NHOkankaku-02, Japan (to T.M.); Spanish Instituto de Salud Carlos III grants PI14/01162 (to I.d.C.) and PI14/0948 (to M.A.M.-P.); Regional Government of Madrid-Spain RAREGENOMICS-CAM grant B2017/BMD3721 (to M.A.M.-P.); and Plan Estatal de I+D+I 2013–2016 with cofunding from the European Regional Development Fund (to I.d.C. and M.A.M.-P.).
ClinGen Hearing Loss Working Group
Hela Azaiez32, Kevin T. Booth32, Richard J. Smith32, Anne B. Giersch33, Cynthia C. Morton33, Xue Z. Liu34, Mustafa Tekin34, Yu Lu35, Huijun Yuan35, Hideki Mutai36, Lisa Schimmenti37