{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:51:03Z","timestamp":1784544663546,"version":"3.55.0"},"reference-count":37,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T00:00:00Z","timestamp":1684195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006447","name":"Universit\u00e4t Z\u00fcrich","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in <jats:italic>HRAS<\/jats:italic>. The vast majority of affected patients share recurring variants affecting <jats:italic>HRAS<\/jats:italic> codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the <jats:italic>HRAS<\/jats:italic> variant c.176C&gt;T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome\u2010like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II\/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS\u2010related RASopathy for patients carrying <jats:italic>HRAS<\/jats:italic> variants affecting codons 58, 59, 60.<\/jats:p>","DOI":"10.1002\/ajmg.a.63240","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T04:49:27Z","timestamp":1684298967000},"page":"2074-2082","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A very mild phenotype in six individuals of a three\u2010generation family with the novel <scp><i>HRAS<\/i><\/scp> variant c.<scp>176C<\/scp>\u2009&gt;\u2009<scp>G<\/scp> p.(<scp>Ala59Gly<\/scp>): Emergence of a new <scp><i>HRAS<\/i><\/scp>\u2010related <scp>RASopathy<\/scp> distinct from <scp>Costello<\/scp> syndrome"],"prefix":"10.1002","volume":"191","author":[{"given":"Tanja","family":"Frey","sequence":"first","affiliation":[{"name":"Institute of Medical Genetics University of Zurich  Zurich 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