{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:43:51Z","timestamp":1787028231908,"version":"build-2736575974"},"reference-count":74,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T00:00:00Z","timestamp":1647561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministry of Education, Universities and Research","doi-asserted-by":"publisher","award":["Law232\/2016"],"award-info":[{"award-number":["Law232\/2016"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease whose causes are unclear. The first ALS gene associated with the autosomal dominant form of the disease was SOD1. This gene has a high rate of rare variants, and an appropriate classification is essential for a correct ALS diagnosis. In this study, we re-evaluated the classification of all previously reported SOD1 variants (n = 202) from ALSoD, project MinE, and in-house databases by applying the ACMG-AMP criteria to ALS. New bioinformatics analysis, frequency rating, and a thorough search for functional studies were performed. We also proposed adjusting criteria strength describing how to apply them to SOD1 variants. Most of the previously reported variants have been reclassified as likely pathogenic and pathogenic based on the modified weight of the PS3 criterion, highlighting how in vivo or in vitro functional studies are determining their interpretation and classification. Furthermore, this study reveals the concordance and discordance of annotations between open databases, indicating the need for expert review to adapt the study of variants to a specific disease. Indeed, in complex diseases, such as ALS, the oligogenic inheritance, the presence of genes that act as risk factors and the reduced penetration must be considered. Overall, the diagnosis of ALS remains clinical, and improving variant classification could support genetic data as diagnostic criteria.<\/jats:p>","DOI":"10.3390\/genes13030537","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:26:22Z","timestamp":1647811582000},"page":"537","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["SOD-1 Variants in Amyotrophic Lateral Sclerosis: Systematic Re-Evaluation According to ACMG-AMP Guidelines"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6246-5901","authenticated-orcid":false,"given":"Paola","family":"Ruffo","sequence":"first","affiliation":[{"name":"Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9255-7492","authenticated-orcid":false,"given":"Benedetta","family":"Perrone","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8364-1783","authenticated-orcid":false,"given":"Francesca Luisa","family":"Conforti","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1111\/bph.15151","article-title":"Amyotrophic lateral sclerosis (ALS), cancer, autoimmunity and metabolic disorders: An unsolved tantalizing challenge","volume":"178","author":"Riancho","year":"2021","journal-title":"Br. 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