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Only 30 patients with <jats:italic>MTOR<\/jats:italic> missense variants are published, including 14 (47%) with the <jats:italic>MTOR<\/jats:italic> c.5395G&gt;A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel <jats:italic>MTOR<\/jats:italic> missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the <jats:italic>MTOR<\/jats:italic> c.5395G&gt;A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (&gt;15%) SKS clinical characteristics and, using these data, proposed guidance for evidence\u2010based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo <jats:italic>MTOR<\/jats:italic> missense variant (absent from population databases) should be considered diagnostic for SKS.<\/jats:p>","DOI":"10.1002\/ajmg.a.62350","type":"journal-article","created":{"date-parts":[[2021,5,25]],"date-time":"2021-05-25T10:21:40Z","timestamp":1621938100000},"page":"2445-2454","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Delineating the <scp>Smith\u2010Kingsmore<\/scp> syndrome phenotype: Investigation of 16 patients with the <scp><i>MTOR<\/i><\/scp> c.<scp>5395G<\/scp>\u00a0&gt;\u2009A p.(<scp>Glu1799Lys<\/scp>) missense variant"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9847-6917","authenticated-orcid":false,"given":"Rebecca L.","family":"Poole","sequence":"first","affiliation":[{"name":"NHS Education for Scotland South East Region, South East of Scotland Clinical Genetics Service  Edinburgh UK"},{"name":"University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippa D. 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