The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes

Lameiras, Ana Rita; Gonçalves, Ana Cláudia; Santos, Ricardo; O’Neill, Assunção; Reis, Luís Roque; Matos, Tiago; Fialho, Graça; Caria, Helena; Escada, Pedro

doi:10.1016/j.ijporl.2015.05.041

Cited by 5 publications

(5 citation statements)

References 29 publications

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“…Due to this, we used the audiometric measures in the Icelandic datasets to estimate the predicted hearing threshold of the carriers in childhood and observed that four of the 55 variants cause prelingual or childhood-onset hearing loss rather than ARHI (“Methods”, Supplementary Data 2 ). Two are variants in GJB2 known to cause deafness 33 , 34 . The other two variants, only detected in Iceland, are fully penetrant loss-of-function variants in known Mendelian deafness genes that have not been described before; a stop-gained variant in heterozygous state in EYA4 (p.Tyr285Ter, MAF = 0.01%, OR = 35.6, P = 1.1 × 10 −7 ; a likelihood-ratio test was performed in all logistic regression associations) and a frameshift variant in homozygous state in OTOA (p.Ala988ArgfsTer3, MAF = 0.65%, OR = 159.60, P = 2.7 × 10 −20 ), where all carriers have moderate to profound hearing loss.…”

Section: Resultsmentioning

confidence: 99%

The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

et al. 2021

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Age-related hearing impairment (ARHI) is the most common sensory disorder in older adults. We conducted a genome-wide association meta-analysis of 121,934 ARHI cases and 591,699 controls from Iceland and the UK. We identified 21 novel sequence variants, of which 13 are rare, under either additive or recessive models. Of special interest are a missense variant in LOXHD1 (MAF = 1.96%) and a tandem duplication in FBF1 covering 4 exons (MAF = 0.22%) associating with ARHI (OR = 3.7 for homozygotes, P = 1.7 × 10−22 and OR = 4.2 for heterozygotes, P = 5.7 × 10−27, respectively). We constructed an ARHI genetic risk score (GRS) using common variants and showed that a common variant GRS can identify individuals at risk comparable to carriers of rare high penetrance variants. Furthermore, we found that ARHI and tinnitus share genetic causes. This study sheds a new light on the genetic architecture of ARHI, through several rare variants in both Mendelian deafness genes and genes not previously linked to hearing.

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Section: Resultsmentioning

confidence: 99%

The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

et al. 2021

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“…Variable expressivity of p.Met34Thr and p.Val37Ile has been reported 16,32 . The hearing loss may be unilateral or bilateral, from mild to profound, affecting different frequency ranges, even in individuals with the same genotype.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

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

Shen

Oza

Castillo

et al. 2019

Genetics in Medicine

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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. Shen et al.

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“…Variable expressivity of Met34Thr and Val37Ile has been reported 16,33 . The hearing loss may be unilateral or bilateral, from mild to profound, affecting different frequency ranges, even in individuals with the same genotype.…”

Section: Genotype-phenotype Correlationmentioning

confidence: 99%

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

Shen

Oza

Castillo

et al. 2018

Preprint

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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 (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. RESULTS: The 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. CONCLUSION: Resolving 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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The controversial p.Met34Thr variant in GJB2 gene: Two siblings, one genotype, two phenotypes

Cited by 5 publications

References 29 publications

The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis

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

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

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