{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:56:08Z","timestamp":1791820568859,"version":"4.3.4"},"reference-count":67,"publisher":"National Academy of Sciences","issue":"46","license":[{"start":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T00:00:00Z","timestamp":1667779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R35-GM134922"],"award-info":[{"award-number":["R35-GM134922"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,11,15]]},"abstract":"<jats:p>\n                    Genetic variants in\n                    <jats:italic>SLC22A5<\/jats:italic>\n                    , encoding the membrane carnitine transporter OCTN2, cause the rare metabolic disorder Carnitine Transporter Deficiency (CTD). CTD is potentially lethal but actionable if detected early, with confirmatory diagnosis involving sequencing of\n                    <jats:italic>SLC22A5<\/jats:italic>\n                    . Interpretation of missense variants of uncertain significance (VUSs) is a major challenge. In this study, we sought to characterize the largest set to date (\n                    <jats:italic>n<\/jats:italic>\n                    = 150) of OCTN2 variants identified in diverse ancestral populations, with the goals of furthering our understanding of the mechanisms leading to OCTN2 loss-of-function (LOF) and creating a protein-specific variant effect prediction model for OCTN2 function. Uptake assays with\n                    <jats:sup>14<\/jats:sup>\n                    C-carnitine revealed that 105 variants (70%) significantly reduced transport of carnitine compared to wild-type OCTN2, and 37 variants (25%) severely reduced function to less than 20%. All ancestral populations harbored LOF variants; 62% of green fluorescent protein (GFP)\u2013tagged variants impaired OCTN2 localization to the plasma membrane of human embryonic kidney (HEK293T) cells, and subcellular localization significantly associated with function, revealing a major LOF mechanism of interest for CTD. With these data, we trained a model to classify variants as functional (&gt;20% function) or LOF (&lt;20% function). Our model outperformed existing state-of-the-art methods as evaluated by multiple performance metrics, with mean area under the receiver operating characteristic curve (AUROC) of 0.895 \u00b1 0.025. In summary, in this study we generated a rich dataset of OCTN2 variant function and localization, revealed important disease-causing mechanisms, and improved upon machine learning\u2013based prediction of OCTN2 variant function to aid in variant interpretation in the diagnosis and treatment of CTD.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2210247119","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T15:17:01Z","timestamp":1667834221000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":27,"title":["Functional genomics of OCTN2 variants informs protein-specific variant effect predictor for Carnitine Transporter Deficiency"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9826-6442","authenticated-orcid":false,"given":"Megan L.","family":"Koleske","sequence":"first","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8033-2499","authenticated-orcid":false,"given":"Gregory","family":"McInnes","sequence":"additional","affiliation":[{"name":"Biomedical Informatics Training Program, Stanford University, Stanford, CA 94305"},{"name":"Empirico Inc., San Diego, CA 92122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8724-693X","authenticated-orcid":false,"given":"Julia E. H.","family":"Brown","sequence":"additional","affiliation":[{"name":"Program in Bioethics, University of California, San Francisco, CA 94143"},{"name":"Institute for Health &amp; Aging, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9089-1921","authenticated-orcid":false,"given":"Neil","family":"Thomas","sequence":"additional","affiliation":[{"name":"Computer Science Division, University of California, Berkeley, CA 94720"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keino","family":"Hutchinson","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, Icahn School of Medicine at Mt. 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Sinai, New York, NY 10029"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata C.","family":"Gallagher","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University of California, San Francisco, CA 94143"},{"name":"Department of Pediatrics, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0734-9868","authenticated-orcid":false,"given":"Yun S.","family":"Song","sequence":"additional","affiliation":[{"name":"Computer Science Division, University of California, Berkeley, CA 94720"},{"name":"Department of Statistics, University of California, Berkeley, CA 94720"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3859-2905","authenticated-orcid":false,"given":"Russ B.","family":"Altman","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Stanford University, Stanford, CA 94305"},{"name":"Department of Genetics, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8041-5430","authenticated-orcid":false,"given":"Kathleen M.","family":"Giacomini","sequence":"additional","affiliation":[{"name":"Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4626"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0022-8"},{"key":"e_1_3_4_3_2","unstructured":"Online Mendelian Inheritance in Man (McKusick-Nathans Institute of Genetic Medicine Johns Hopkins University Baltimore MD)."},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(97)70171-9"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12158"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","unstructured":"R. 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Koleske \u201cLarge-scale mutational analysis of transporters in the Solute Carrier Family 22: Applications in rare disease and pharmacogenetics \u201d PhD thesis University of California San\u00a0Francisco CA (2022)."},{"key":"e_1_3_4_67_2","unstructured":"M. L. Koleske SUB12121751. ClinVar. https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/?gr=0&term=SUB12121751. 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