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These <jats:italic>CACNA1D<\/jats:italic> variants have been identified somatically in aldosterone-producing adenomas as well as germline in patients with neurodevelopmental and in some cases endocrine symptoms. In vitro studies in heterologous expression systems have revealed typical gating changes that indicate enhanced Ca<jats:sup>2+<\/jats:sup> influx through Cav1.3 channels as the underlying disease-causing mechanism. Here we summarize the clinical findings of 12 well-characterized individuals with a total of 9 high-risk pathogenic <jats:italic>CACNA1D<\/jats:italic> variants. Moreover, we propose how information from somatic mutations in aldosterone-producing adenomas could be used to predict the potential pathogenicity of novel germline variants. Since these pathogenic de novo variants can cause a channel-gain-of function, we also discuss the use of L-type Ca<jats:sup>2+<\/jats:sup> channel blockers as a potential therapeutic option.<\/jats:p>","DOI":"10.1007\/s00424-020-02418-w","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T11:02:48Z","timestamp":1592996568000},"page":"755-773","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["De novo CACAN1D Ca2+ channelopathies: clinical phenotypes and molecular mechanism"],"prefix":"10.1007","volume":"472","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3882-3283","authenticated-orcid":false,"given":"Nadine J.","family":"Ortner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Kaserer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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