{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:02:39Z","timestamp":1783483359667,"version":"3.55.0"},"reference-count":14,"publisher":"Bioscientifica","issue":"6","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":2302,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Background: Resistance to thyroid hormone beta (RTH\u03b2) is characterized by elevated thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), caused by thyroid hormone receptor beta gene (THRB) defects. Most mutations producing RTH\u03b2 phenotype are located in CG-rich regions of THRB, encoding the T3-binding and hinge domains of the receptor. However, a region encompassing codons 384\u2013425 is virtually devoid of RTH\u03b2-causing mutations, termed \u201ccold region.\u201d Case: A 49-year-old woman was diagnosed with Hashimoto thyroiditis in her twenties, and levothyroxine (LT4) was initiated. During LT4 treatment she had slightly elevated free thyroxine and TSH levels, suggesting the possibility of RTH\u03b2. Results: Sequencing of THRB identified a heterozygous missense variant c.1154G&amp;gt;A producing p.G385E in the proband. Since this variant of unknown significance (VUS) has not been reported in RTH\u03b2 individuals and considering its location in the \u201ccold region\u201d of THRB, we questioned its relevance. In silico functional prediction algorithms showed conflicting results: PolyPhen-2 predicted this VUS to be probably damaging with a score of 1.000, while SIFT predicted it to be tolerated with a score of 0.07, thus making additional investigations necessary. Genotyping of family members revealed that the proband\u2019s mother and sister, without RTH\u03b2 phenotype, also harbored the same variant. This indicates that the THRB G385E variant is unlikely to manifest RTH\u03b2 phenotype and confirms its \u201ccold\u201d status. Conclusions: This study illustrates that assigning causality of a THRB VUS for RTH\u03b2 based only on in silico prediction algorithms is not always fully reliable. Additional phenotype-genotype segregation in family members can assist in predicting functional consequences of missense mutations.<\/jats:p>","DOI":"10.1159\/000503860","type":"journal-article","created":{"date-parts":[[2019,10,30]],"date-time":"2019-10-30T18:00:39Z","timestamp":1572458439000},"page":"293-297","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-17","source":"Crossref","is-referenced-by-count":7,"title":["A Novel G385E Variant in the Cold Region of the T3-Binding Domain of Thyroid Hormone Receptor Beta Gene and Investigations to Assess Its Clinical Significance"],"prefix":"10.1530","volume":"8","author":[{"given":"Manassawee","family":"Korwutthikulrangsri","sequence":"first","affiliation":[{"name":"1Department of Medicine, University of Chicago, Chicago, Illinois, USA"},{"name":"2Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysoula","family":"Dosiou","sequence":"additional","affiliation":[{"name":"3Department of Medicine, Stanford University School of Medicine, Stanford, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2743-770X","authenticated-orcid":false,"given":"Alexandra\u00a0M.","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"1Department of Medicine, University of Chicago, Chicago, Illinois, USA"},{"name":"4Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"1Department of Medicine, University of Chicago, Chicago, Illinois, USA"},{"name":"5Department of Pediatrics, University of Chicago, Chicago, Illinois, USA"},{"name":"6Committee on Genetics, University of Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2019,10,30]]},"reference":[{"issue":"6","key":"2026070712582385800_ref1","doi-asserted-by":"publisher","first-page":"2408","DOI":"10.1172\/JCI116474","article-title":"Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor beta gene. 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