{"id":17027,"date":"2025-03-17T11:16:47","date_gmt":"2025-03-17T11:16:47","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=17027"},"modified":"2025-03-17T11:16:47","modified_gmt":"2025-03-17T11:16:47","slug":"2025-cohort-scale-automated-patch-clamp-data-improves-variant-classification-and-penetrance-stratification-for-scn5a-brugada-syndrome","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2025-cohort-scale-automated-patch-clamp-data-improves-variant-classification-and-penetrance-stratification-for-scn5a-brugada-syndrome\/","title":{"rendered":"2025 &#8211; Cohort-scale automated patch clamp data improves variant classification and penetrance stratification for SCN5A-Brugada Syndrome"},"content":{"rendered":"<p>Background: Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel Na<sub>V<\/sub>1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and\/or incomplete penetrance. Methods: We analyzed all 252 missense and in-frame insertion\/deletion SCN5A variants from a previously published large cohort of BrS cases (n=3,335 patients) using a calibrated high-throughput automated patch clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hot-spot, case counts, protein length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD. Results: Most variants (146\/252) were functionally abnormal (Z \u2264 \u22122), with 100 having severe loss-of-function (Z \u2264 \u22124). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z \u2264 \u22126 had penetrance of 24.5% (15.9 \u2212 37.7% CI) and an odds ratio of 501 for BrS. Conclusions: This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function \u2033bystander\u2033 variants that have a low risk for BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[143,254],"target_categories":[61],"target_families":[340],"targets":[],"resource_keyword":[],"class_list":["post-17027","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-drug-discovery","therapeutic_areas-assay-development-and-validation","therapeutic_areas-rare-diseases","target_categories-voltage-gated-ion-channels","target_families-cav-channels"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/17027","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=17027"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=17027"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=17027"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=17027"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=17027"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=17027"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=17027"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=17027"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=17027"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}