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guidance program","award":["SHWJRS2021-99"],"award-info":[{"award-number":["SHWJRS2021-99"]}]},{"name":"Shanghai \u201cRising Stars of Medical Talent\u201d Youth Development Program-Outstanding Youth Medical Talents","award":["82273233"],"award-info":[{"award-number":["82273233"]}]},{"name":"Shanghai \u201cRising Stars of Medical Talent\u201d Youth Development Program-Outstanding Youth Medical Talents","award":["81772777"],"award-info":[{"award-number":["81772777"]}]},{"name":"Shanghai \u201cRising Stars of Medical Talent\u201d Youth Development Program-Outstanding Youth Medical Talents","award":["22ZR1408900"],"award-info":[{"award-number":["22ZR1408900"]}]},{"name":"Shanghai \u201cRising Stars of Medical Talent\u201d Youth Development Program-Outstanding Youth Medical Talents","award":["SHDC2020CR4079"],"award-info":[{"award-number":["SHDC2020CR4079"]}]},{"name":"Shanghai \u201cRising Stars of Medical Talent\u201d Youth Development Program-Outstanding Youth Medical 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Loss of function variant of FH gene inactivates the Kreb\u2019s cycle enzyme activity and predisposes individuals with such variant to the development of HLRCC. Methods: Next-generation sequencing (NGS) and Sanger confirmation were given to family members accessible. Following that, a functional study in vitro was performed to further confirm the pathogenicity of the variant. FH-Wild type (FH-WT) and FH-mutant (FH-MUT) (E378K) plasmid were constructed and transfected into 293T and uterine leiomyoma cell lines, respectively. Proliferation assessment was executed to show how this mutation affects the growth of uterine leiomyoma. qPCR and Western blotting were performed to investigate the change of transcription and translation of FH with mutation (E378K), and FH enzyme assay activity were tested in 293T cells with mutation and wild-type plasmids. Results: Here, we presented two families with the same missense variant (c.1132G &gt; A) that has not been reported as a germline mutation in hereditary uterine leiomyomas before and classified as VUS in gene databases. Our in vitro experiments supported the pathogenicity of this missense variant, especially in uterine leiomyomata. Conclusions: According to the American College of Medical Genetics (ACMG) guideline, the E378K variant was classified as likely pathogenic (with evidence PS4_support, PS3_support, PM2_support, PP1, PP3 and PP4 evidence). Further insights into clinical management in uterine leiomyomata were discussed and should be practiced in gynecological clinical settings.<\/jats:p>","DOI":"10.3390\/genes14030744","type":"journal-article","created":{"date-parts":[[2023,3,20]],"date-time":"2023-03-20T05:46:42Z","timestamp":1679291202000},"page":"744","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A Missense Mutation c.1132G &gt; A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata"],"prefix":"10.3390","volume":"14","author":[{"given":"Yue","family":"Shi","sequence":"first","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojun","family":"Ren","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Kang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"},{"name":"Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3387","DOI":"10.1073\/pnas.051633798","article-title":"Inherited susceptibility to uterine leiomyomas and renal cell cancer","volume":"98","author":"Launonen","year":"2001","journal-title":"Proc. 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