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Germline pathogenic variants in <jats:italic>NOTCH1<\/jats:italic> predispose to a spectrum of cardiovascular malformations including Adams\u2010Oliver syndrome and a wide variety of isolated complex and simple congenital heart defects. The intracellular C\u2010terminus of the single\u2010pass transmembrane receptor encoded by <jats:italic>NOTCH1<\/jats:italic> contains a transcriptional activating domain (TAD) required for target gene activation and a PEST domain (a sequence rich in proline, glutamic acid, serine, and threonine), regulating protein stability and turnover. We present a patient with a novel variant encoding a truncated NOTCH1 protein without the TAD and PEST domain (NM_017617.4: c.[6626_6629del];[=], p.(Tyr2209CysfsTer38)) and extensive cardiovascular abnormalities consistent with a <jats:italic>NOTCH1<\/jats:italic>\u2010mediated mechanism. This variant fails to promote transcription of target genes as assessed by luciferase reporter assay. Given the roles of the TAD and PEST domains in NOTCH1 function and regulation, we hypothesize that loss of both the TAD and the PEST domain results in a stable, loss\u2010of\u2010function protein that acts as an antimorph through competition with wild\u2010type NOTCH1.<\/jats:p>","DOI":"10.1002\/ajmg.a.63167","type":"journal-article","created":{"date-parts":[[2023,3,3]],"date-time":"2023-03-03T11:58:31Z","timestamp":1677844711000},"page":"1593-1598","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp><i>NOTCH1<\/i><\/scp> loss of the <scp>TAD<\/scp> and <scp>PEST<\/scp> domain: An antimorph?"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9624-0399","authenticated-orcid":false,"given":"Pierre","family":"Boerkoel","sequence":"first","affiliation":[{"name":"MD Undergraduate Program University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Huynh","sequence":"additional","affiliation":[{"name":"Provincial Medical Genetics Program B.C. Women's Hospital  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui Xiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University of British Columbia  Vancouver British Columbia Canada"},{"name":"BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius F.","family":"Boerkoel","sequence":"additional","affiliation":[{"name":"Provincial Medical Genetics Program B.C. 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Women's Hospital  Vancouver British Columbia Canada"},{"name":"Department of Medical Genetics University of British Columbia  Vancouver British Columbia Canada"},{"name":"BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lehman","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics University of British Columbia  Vancouver British Columbia Canada"},{"name":"BC Children's Hospital Research Institute University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jefferson","family":"Terry","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine University of British Columbia and BC Children's Hospital  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne","family":"Elbert","sequence":"additional","affiliation":[{"name":"Provincial Medical Genetics Program B.C. 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