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Specifically, <jats:italic>SETD2<\/jats:italic> is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of \u03b1\u2010tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan\u2010Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of <jats:italic>SETD2<\/jats:italic> whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C&gt;T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G&gt;A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of <jats:italic>SETD2<\/jats:italic>, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C&gt;T p.(Arg1740Trp) in <jats:italic>SETD2.<\/jats:italic><\/jats:p>","DOI":"10.1002\/ajmg.a.61724","type":"journal-article","created":{"date-parts":[[2020,7,25]],"date-time":"2020-07-25T06:24:45Z","timestamp":1595658285000},"page":"2037-2048","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Genotype\u2013phenotype correlation at codon 1740 of <scp><i>SETD2<\/i><\/scp>"],"prefix":"10.1002","volume":"182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4906-7428","authenticated-orcid":false,"given":"Rachel","family":"Rabin","sequence":"first","affiliation":[{"name":"Clinical Genetic Services, Department of Pediatrics NYU School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Radmanesh","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neuroradiology, Department of Radiology NYU School of Medicine  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A.","family":"Glass","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Pediatrics, Division of Medical Genetics University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7681-2844","authenticated-orcid":false,"given":"William B.","family":"Dobyns","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Pediatrics, Division of Medical Genetics University of Washington  Seattle Washington USA"},{"name":"Department of Neurology University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly A.","family":"Aldinger","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph T.","family":"Shieh","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, Division of Medical Genetics, Department of Pediatrics Benioff Children's Hospital, University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelby","family":"Romoser","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics University of Iowa Hospitals  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Bombei","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics and Genomics, Stead Family Department of Pediatrics University of Iowa Hospitals  Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8095-9793","authenticated-orcid":false,"given":"Leah","family":"Dowsett","sequence":"additional","affiliation":[{"name":"Kapi'olani Medical Specialists and Department of Pediatrics University of Hawai'i John A. 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