BACKGROUND Familial Mediterranean fever is a hereditary inflammatory disorder caused by variants in MEFV. c.2230G>T p.(Ala744Ser) rs61732874 is considered to be an established pathogenic variant in MEFV, but in this study we provide a complete evaluation that suggests this variant is likely benign. METHODS Using an in-house exome database from 924 individuals, we extracted all individuals harboring this variant for clinical, laboratory, and familial evaluation. RESULTS We identified the variant in 58 individuals from 39 families. The allele frequency of this variant in our database is 4.2%. None of the identified individuals match the diagnosis of Familial Mediterranean Fever. Using the American College of Medical Genetics and Genomics guidelines for variant classification, this variant is classified as likely benign and not pathogenic. CONCLUSION Conflicting evidence about variants creates challenges for testing laboratories and impacts patient care. Sharing information drawn mainly from underrepresented populations and clinical phenotyping are important tools for precise curation of genetic variants.

中文翻译：

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MEFV c.2230G>T p.(Ala744Ser) rs61732874 之前由于缺乏特定人群数据库而被错误分类为致病性变异

背景家族性地中海热是一种由MEFV变异引起的遗传性炎症性疾病。c.2230G>T p.(Ala744Ser) rs61732874 被认为是 MEFV 中已确定的致病变异，但在本研究中，我们提供了一个完整的评估，表明该变异可能是良性的。方法使用来自 924 名个体的内部外显子组数据库，我们提取了所有携带该变异的个体，用于临床、实验室和家族评估。结果 我们在 39 个家庭的 58 个个体中鉴定了该变异。我们数据库中该变体的等位基因频率为 4.2%。已确定的个体均不符合家族性地中海热的诊断。使用美国医学遗传学和基因组学学会的变异分类指南，该变异被归类为可能是良性的而非致病性的。结论 关于变异的相互矛盾的证据给测试实验室带来了挑战并影响了患者护理。共享主要来自代表性不足的人群和临床表型的信息是精确控制遗传变异的重要工具。