{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:23:16Z","timestamp":1772252596155,"version":"3.50.1"},"reference-count":19,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T00:00:00Z","timestamp":1603324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Federation Ministry of Health","award":["056-00016-18-04"],"award-info":[{"award-number":["056-00016-18-04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Osteopetrosis is a group of rare inheritable disorders of the skeleton characterized by increased bone density. The disease is remarkably heterogeneous in clinical presentation and often misdiagnosed. Therefore, genetic testing and molecular pathogenicity analysis are essential for precise diagnosis and new targets for preventive pharmacotherapy. Mutations in the CLCN7 gene give rise to the complete spectrum of osteopetrosis phenotypes and are responsible for about 75% of cases of autosomal dominant osteopetrosis. In this study, we report the identification of a novel variant in the CLCN7 gene in a patient diagnosed with osteopetrosis and provide evidence for its significance (likely deleterious) based on extensive comparative genomics, protein sequence and structure analysis. A set of automated bioinformatics tools used to predict consequences of this variant identified it as deleterious or pathogenic. Structure analysis revealed that the variant is located at the same \u201chot spot\u201d as the most common CLCN7 mutations causing osteopetrosis. Deep phylogenetic reconstruction showed that not only Leu614Arg, but any non-aliphatic substitutions in this position are evolutionarily intolerant, further supporting the deleterious nature of the variant. The present study provides further evidence that reconstructing a precise evolutionary history of a gene helps in predicting phenotypical consequences of variants of uncertain significance.<\/jats:p>","DOI":"10.3390\/genes11111242","type":"journal-article","created":{"date-parts":[[2020,10,22]],"date-time":"2020-10-22T20:51:00Z","timestamp":1603399860000},"page":"1242","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Identification and Characterization of a Novel CLCN7 Variant Associated with Osteopetrosis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5849-1311","authenticated-orcid":false,"given":"Dmitrii S.","family":"Bug","sequence":"first","affiliation":[{"name":"Bioinformatics Research Center, Pavlov First Saint Petersburg Medical State University, St. Petersburg 197022, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ildar M.","family":"Barkhatov","sequence":"additional","affiliation":[{"name":"R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation, Pavlov First Saint Petersburg State Medical University, St. Petersburg 197022, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yana V.","family":"Gudozhnikova","sequence":"additional","affiliation":[{"name":"Pavlov First Saint Petersburg State Medical University Clinic, St. Petersburg 197022, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Artem V.","family":"Tishkov","sequence":"additional","affiliation":[{"name":"Bioinformatics Research Center, Pavlov First Saint Petersburg Medical State University, St. Petersburg 197022, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6708-5323","authenticated-orcid":false,"given":"Igor B.","family":"Zhulin","sequence":"additional","affiliation":[{"name":"Bioinformatics Research Center, Pavlov First Saint Petersburg Medical State University, St. Petersburg 197022, Russia"},{"name":"Department of Microbiology and Translational Data Analytics Institute, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6397-824X","authenticated-orcid":false,"given":"Natalia V.","family":"Petukhova","sequence":"additional","affiliation":[{"name":"Bioinformatics Research Center, Pavlov First Saint Petersburg Medical State University, St. Petersburg 197022, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,22]]},"reference":[{"key":"ref_1","first-page":"5","article-title":"Osteopetrosis. 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