{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T18:28:50Z","timestamp":1754159330355,"version":"3.41.2"},"reference-count":30,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2022A1515220126"],"award-info":[{"award-number":["2022A1515220126"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012151","name":"Sanming Project of Medicine in Shenzen Municipality","doi-asserted-by":"publisher","award":["SZSM202311005"],"award-info":[{"award-number":["SZSM202311005"]}],"id":[{"id":"10.13039\/501100012151","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Very\u2013long\u2010chain acyl\u2010CoA dehydrogenase deficiency (VLCADD) is a rare disorder of long\u2010chain mitochondrial fatty acid oxidation (FAO) caused by biallelic mutations in the acyl\u2010CoA dehydrogenase very\u2013long\u2010chain (<jats:italic>ACADVL<\/jats:italic>) gene with autosomal recessive (AR) inheritance. Currently, the <jats:italic>ACADVL<\/jats:italic> gene has over 350 VUSs in the ClinVar database that require characterization to determine potential pathogenicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, we performed functional studies and three\u2010dimensional protein structure analysis to identify the pathogenicity of two <jats:italic>ACADVL<\/jats:italic> VUSs in a Chinese VLCADD patient with severe clinical symptoms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Biallelic variants in <jats:italic>ACADVL<\/jats:italic> gene c.1055T&gt;C (p.Met352Thr) and c.1269G&gt;A (p.Ser423=) were identified by whole\u2010genome sequencing (WGS) and confirmed using Sanger sequencing. Both variants were recorded in ClinVar database with \u201cconflicting interpretation of its pathogenicity\u201d and need appropriate evidence for reclassification to guide family reproductive planning. Synonymous variant p.Ser423= could result in skipping of exon 12 through mini\u2010gene splicing experiment testing. Further functional studies reveal that both variants yield a mild\u2010to\u2010severe decrease in <jats:italic>ACADVL<\/jats:italic> mRNA and protein expression in\u00a0vitro.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In this study, we determined the pathogenicity of <jats:italic>ACADVL<\/jats:italic> variants c.1055T&gt;C (p.Met352Thr) and c.1269G&gt;A (p.Ser423=) via experimental and <jats:italic>in silico<\/jats:italic> analysis. The findings contribute to expanding the variant spectrum in the <jats:italic>ACADVL<\/jats:italic> gene, and exploring the pathogenicity of VUS may provide us with further understanding of the disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70120","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T10:34:48Z","timestamp":1752834888000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of Variants of Uncertain Significance in <scp><i>ACADVL<\/i><\/scp> Gene From a Very\u2013Long\u2010Chain Acyl\u2010<scp>CoA<\/scp> Dehydrogenase Deficiency Patient"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4801-4842","authenticated-orcid":false,"given":"Qin","family":"Wang","sequence":"first","affiliation":[{"name":"Shenzhen Maternity and Child Healthcare Hospital Southern Medical University  Shenzhen Guangdong Province 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