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SRY induces significant upregulation of <jats:italic>SOX9<\/jats:italic> expression in XY gonads. Loss\u2010of\u2010function <jats:italic>SOX9<\/jats:italic> variants cause testicular dysgenesis in 46,XY patients, while duplication of the total gene or the upstream regulatory region results in testicular development in 46,XX patients. However, gain\u2010of\u2010function (GoF) <jats:italic>SOX9<\/jats:italic> variants have not been reported previously. We report the case of a 16\u2010year\u2010old female patient with a 46,XX karyotype who had masculinized external genitalia and unilateral ovotestis. Next\u2010generation sequencing\u2010based genetic screening for disorders of sex development led to the identification of a novel <jats:italic>SOX9<\/jats:italic> variant (p.Glu50Lys), transmitted from the phenotypically normal father. Expression analysis showed that E50K\u2010SOX9 enhanced transactivation of the luciferase reporter containing the testis enhancer sequence core element compared with that containing the wildtype\u2010SOX9. This GoF activity was not observed in the luciferase reporter containing <jats:italic>Amh<\/jats:italic>, the gene for anti\u2010M\u00fcllerian hormone. We genetically engineered female mice (<jats:italic>Sox9<\/jats:italic><jats:sup>E50K\/E50K<\/jats:sup>), and they showed no abnormalities in the external genitalia or ovaries. In conclusion, a novel <jats:italic>SOX9<\/jats:italic> variant with a promoter\u2010specific GoF activity was identified in vitro; however, the disease phenotype was not recapitulated by the mouse model. At present, the association between the GoF <jats:italic>SOX9<\/jats:italic> variant and the ovotestis phenotype remains unclear. Future studies are needed to verify the possible association.<\/jats:p>","DOI":"10.1002\/ajmg.a.62063","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T03:49:04Z","timestamp":1609904944000},"page":"1067-1075","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification of the first <scp>promoter\u2010specific gain\u2010of\u2010function <i>SOX9<\/i><\/scp> missense variant (p.<scp>E50K<\/scp>) in a patient with 46,<scp>XX<\/scp> ovotesticular disorder of sex development"],"prefix":"10.1002","volume":"185","author":[{"given":"Kikumi","family":"Ushijima","sequence":"first","affiliation":[{"name":"Department of Molecular Endocrinology National Research Institute for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuya","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Systems BioMedicine 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