PDF(Pubmed)
Abstract：
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The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants.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.
The ClinGen Hearing Loss Expert Panel collected published data and shared unpublished information from contributing laboratories and clinics regarding the two variants.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.
摘要：
GJB2的致病变异是常染色体隐性隐性感觉神经性听力损失的最常见原因。分类c.101T>C/p。Met34Thr和c.109G>A/p。GJB2中的Val37Ile是有争议的。因此,这两种变体的解释需要专家共识。
ClinGen听力损失专家小组收集了已发表的数据，并从有贡献的实验室和诊所分享了关于这两种变体的未发表的信息。Functional,计算，等位基因,并获得了分离数据。进行病例对照统计分析。
小组审查了综合信息，并利用专业变体解释指南和专业判断对p.Met34Thr和p.Val37Ile变体进行分类。我们发现，p.Met34Thr和p.Val37Ile在听力损失患者中的代表性明显过高，与人口对照相比。p.Met34Thr或p.Val37Ile的纯合或复合杂合个体通常表现出轻度至中度听力损失。其他几种类型的证据也支持这两种变体的致病作用。
解决变体分类中的争议需要国际多机构专家小组之间的协调努力来共享数据，规范分类准则，审查证据,达成共识。我们得出的结论是，GJB2中的p.Met34Thr和p.Val37Ile变体是常染色体隐性遗传非综合征性听力损失的致病性，具有可变的表达和不完全的外显率。
ClinGen听力损失专家小组收集了已发表的数据，并从有贡献的实验室和诊所分享了关于这两种变体的未发表的信息。
小组审查了综合信息，
解决变体分类中的争议需要国际多机构专家小组之间的协调努力来共享数据，
