Thyroglobulin (TG) is a large glycosylated protein of 2767 amino acids, secreted by the thyrocytes into the follicular lumen. It plays an essential role in the process of thyroid hormone synthesis. TG gene variants lead to permanent congenital hypothyroidism. In the present work, we report a detailed population and bioinformatic prediction analyses of the TG variants indexed in the Genome Aggregation Database (gnomAD). The results showed a clear predominance of nonsense variants in the European (Finnish), European (Non-Finnish) and Ashkenazi Jewish ethnic groups, whereas the splice site variants predominate in South Asian and African/African-American populations. In total, 282 novel TG variants were described (47 missense involving the wild-type cysteine residues, 177 missense located in the ChEL domain and 58 splice site variants) which were not reported in the literature and that would have deleterious effects in prediction programs. In the gnomAD population, the estimated prevalence of heterozygous carriers of the potentially damaging variants was 1:320.

In conclusion, we provide an updated and curated reference source for the diagnosis of thyroid disease, mainly to congenital hypothyroidism due to TG deficiency. The identification and characterization of TG variants is undoubtedly a valuable approach to study the TG structure/function relations and an important tool for clinical diagnosis and genetic counseling.

甲状腺球蛋白 (TG) 是一种含有 2767 个氨基酸的大糖基化蛋白，由甲状腺细胞分泌到滤泡腔中。它在甲状腺激素合成过程中起着至关重要的作用。TG基因变异导致永久性先天性甲状腺功能减退。在目前的工作中，我们报告了基因组聚合数据库 (gnomAD) 中索引的TG变体的详细种群和生物信息学预测分析。结果显示，在欧洲（芬兰）、欧洲（非芬兰）和德系犹太人族群中，无义变体明显占优势，而剪接位点变体在南亚和非洲/非洲裔美国人中占主导地位。总共282个小说TG描述了变体（涉及野生型半胱氨酸残基的 47 个错义，位于 ChEL 结构域的 177 个错义和 58 个剪接位点变体），这些变体在文献中没有报道，并且会对预测程序产生有害影响。在 gnomAD 人群中，具有潜在破坏性变异的杂合子携带者的估计患病率为 1:320。

总之，我们为甲状腺疾病的诊断提供了更新和精选的参考来源，主要是由于 TG 缺乏导致的先天性甲状腺功能减退症。TG变异体的鉴定和表征无疑是研究TG结构/功能关系的一种有价值的方法，也是临床诊断和遗传咨询的重要工具。