{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:24:29Z","timestamp":1787318669582,"version":"build-2736575974"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      . Interpreting the pathogenicity of\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      missense variants is challenging, and \u224879% of\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      An in vitro\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      \u2013Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      loss-of-function.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak\n                      <jats:italic toggle=\"yes\">I<\/jats:italic>\n                      <jats:sub>Na<\/jats:sub>\n                      density (\n                      <jats:italic toggle=\"yes\">R<\/jats:italic>\n                      <jats:sup>2<\/jats:sup>\n                      =0.86). The assay accurately distinguished benign controls (24\/25 concordant variants) from pathogenic controls (23\/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics\/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      variants of uncertain significance revealed loss-of-function for 3\/4 variants, enabling reclassification to likely pathogenic.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future\n                      <jats:italic toggle=\"yes\">SCN5A<\/jats:italic>\n                      \u2013Brugada syndrome variants of uncertain significance.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.124.004569","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T05:01:45Z","timestamp":1719896505000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Multisite Validation of a Functional Assay to Adjudicate\n                    <i>SCN5A<\/i>\n                    Brugada Syndrome\u2013Associated Variants"],"prefix":"10.1161","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1616-5681","authenticated-orcid":true,"given":"Joanne G.","family":"Ma","sequence":"first","affiliation":[{"name":"Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia (J.G.M., J.I.V., C.-A.N.)."},{"name":"School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia (J.G.M., J.I.V., C.-A.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2014-7950","authenticated-orcid":true,"given":"Matthew J.","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Vanderbilt University School of Medicine, Nashville, TN (M.J.O., A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4260-7356","authenticated-orcid":true,"given":"Ebony","family":"Richardson","sequence":"additional","affiliation":[{"name":"Clinical Genomics Laboratory, Center for Population Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia (E.R., J.I.)"},{"name":"Murdoch Children\u2019s Research Institute, Melbourne, Victoria, Australia (E.R., J.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-3431","authenticated-orcid":true,"given":"Kate L.","family":"Thomson","sequence":"additional","affiliation":[{"name":"Oxford Genetics Laboratories, Churchill Hospital, Oxford, United Kingdom (K.L.T.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4846-7676","authenticated-orcid":true,"given":"Jodie","family":"Ingles","sequence":"additional","affiliation":[{"name":"Clinical Genomics Laboratory, Center for Population Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia (E.R., J.I.)"},{"name":"Murdoch Children\u2019s Research Institute, Melbourne, Victoria, Australia (E.R., J.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0870-2923","authenticated-orcid":true,"given":"Ayesha","family":"Muhammad","sequence":"additional","affiliation":[{"name":"Vanderbilt University School of Medicine, Nashville, TN (M.J.O., A.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph F.","family":"Solus","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (Van-CART), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (J.F.S., G.D., M.B.S., D.M.R., A.M.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2771-6466","authenticated-orcid":true,"given":"Giovanni","family":"Davogustto","sequence":"additional","affiliation":[{"name":"Vanderbilt Center for Arrhythmia Research and Therapeutics (Van-CART), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (J.F.S., G.D., M.B.S., D.M.R., A.M.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1380-8493","authenticated-orcid":true,"given":"Katherine C.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6824-7155","authenticated-orcid":true,"given":"M. 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