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Our aim was to characterize the p.Leu2286Val variant in 17 Basque patients, to accurately determine its correlation with clinical features and to explore the possible founder effect of the variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Families harbouring the p.Leu2286 <jats:italic>RYR1<\/jats:italic> variant underwent a detailed clinical evaluation, including muscle magnetic resonance imaging, electromyography and muscle biopsy. Haplotypes were analysed in available patients and their relatives.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Individuals carrying the p.Leu2286Val shared a common haplotype, suggesting a founder event in the Basque Country population. The most prevalent features were exertional myalgia, high creatine kinase (CK) levels, cramps and muscle hypertrophy. None of the patients carrying only the p.Leu2286Val showed progression to severe muscle weakness and muscle magnetic resonance imaging showed a heterogeneous muscle involvement. Muscle biopsy revealed non\u2010specific findings in two patients and features associated with central core disease in one patient carrying only the p.Leu2286Val and two patients harbouring an additional <jats:italic>RYR1<\/jats:italic> variant. Three individuals carrying an in <jats:italic>trans RYR1<\/jats:italic> variant presented with an earlier onset and more severe phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Here, it is shown that the dominantly inherited p.Leu2286Val <jats:italic>RYR1<\/jats:italic> founder variant is associated with a milder phenotype of exercise intolerance, myalgia and hyperCKemia.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.16471","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T11:39:01Z","timestamp":1735731541000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A founder variant in the <scp><i>RYR1<\/i><\/scp> gene is associated with <scp>hyperCKemia<\/scp>, myalgia and muscle cramps"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5185-5031","authenticated-orcid":false,"given":"Alba","family":"Segarra\u2010Casas","sequence":"first","affiliation":[{"name":"Genetics Department, Institut de Recerca Sant Pau (IR SANT PAU) Hospital de la Santa Creu i Sant Pau  Barcelona Spain"},{"name":"Genetics and Microbiology Department Universitat Auton\u00f2ma de Barcelona  Bellaterra Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Iruzubieta","sequence":"additional","affiliation":[{"name":"Group of Neuromuscular Diseases, Donostia University Hospital Biodonostia\u2010Biogipuzkoa Health Research Institute  Donostia\u2010San Sebasti\u00e1n Spain"},{"name":"CIBERNED Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas\u2010Instituto de Salud Carlos III (CIBER\u2010CIBERNED\u2010ISCIII)  Madrid Spain"},{"name":"Faculty of Medicine University of Deusto  Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solange","family":"Kapetanovic","sequence":"additional","affiliation":[{"name":"ALS and Neuromuscular Unit, Department of Neurology Hospital Universitario Basurto  Bilbao Spain"},{"name":"Nucleic Acid Therapeutics for Rare Diseases\u2013NAT\u2010RD Biobizkaia Basque Health Research Institute (IIS Biobizkaia)  Barakaldo Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aurelio","family":"Hern\u00e1ndez\u2010La\u00edn","sequence":"additional","affiliation":[{"name":"Neuropathology Unit, imas12 Research Institute Hospital Universitario 12 de Octubre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivonne","family":"Jeric\u00f3","sequence":"additional","affiliation":[{"name":"Department of Neurology, Neuromuscular and Motor Neuron Research Group, Navarra Health Research Institute (IdisNA) Hospital Universitario de Navarra  Pamplona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Fern\u00e1ndez\u2010Torr\u00f3n","sequence":"additional","affiliation":[{"name":"Group of Neuromuscular Diseases, Donostia University Hospital Biodonostia\u2010Biogipuzkoa Health Research Institute  Donostia\u2010San Sebasti\u00e1n Spain"},{"name":"CIBERNED Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas\u2010Instituto de Salud Carlos III (CIBER\u2010CIBERNED\u2010ISCIII)  Madrid Spain"},{"name":"Faculty of Medicine University of Deusto  Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miren","family":"Maneiro","sequence":"additional","affiliation":[{"name":"Group of Neuromuscular Diseases, Donostia University Hospital Biodonostia\u2010Biogipuzkoa Health Research Institute  Donostia\u2010San Sebasti\u00e1n Spain"},{"name":"CIBERNED Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas\u2010Instituto de Salud Carlos III (CIBER\u2010CIBERNED\u2010ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-9031","authenticated-orcid":false,"given":"Pablo","family":"Marco\u2010Moreno","sequence":"additional","affiliation":[{"name":"Group of Neuromuscular Diseases, Donostia University Hospital Biodonostia\u2010Biogipuzkoa Health Research Institute  Donostia\u2010San Sebasti\u00e1n Spain"},{"name":"CIBERNED Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Neurodegenerativas\u2010Instituto de Salud Carlos III (CIBER\u2010CIBERNED\u2010ISCIII)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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