<i>SCN5A</i>‐C683R exhibits combined gain‐of‐function and loss‐of‐function properties related to adrenaline‐triggered ventricular arrhythmia
Bibliographic record
Abstract
New Findings What is the role of SCN5A‐C683R? SCN5A‐C683R is a novel variant associated with an uncommon phenotype of adrenaline‐triggered ventricular arrhythmia in the absence of a distinct ECG phenotype. What is the main finding and its importance? Functional studies demonstrated that NaV1.5/C683R results in a mixed electrophysiological phenotype with gain‐of‐function (GOF) and loss‐of‐function (LOF) properties compared with NaV1.5/wild type. Gain‐of‐function properties are characterized by a significant increase of the maximal current density and a hyperpolarizing shift of the steady‐state activation. The LOF effect of NaV1.5/C683R is characterized by increased closed‐state inactivation. Electrophysiological properties and clinical manifestation of SCN5A‐C683R are different from long‐QT‐3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome. Abstract Mutations of SCN5Ahave been identified as the genetic substrate of various inherited arrhythmia syndromes, including long‐QT‐3 and Brugada syndrome. We recently identified a novel SCN5A variant (C683R) in two genetically unrelated families. The index patients of both families experienced adrenaline‐triggered ventricular arrhythmia with cardiac arrest but did not show a specific ECG phenotype, raising the hypothesis that SCN5A‐C683R might be a susceptibility variant and the genetic substrate of distinct inherited arrhythmia. We conducted functional cellular studies to characterize the electrophysiological properties of NaV1.5/C683R in order to explore the potential pathogenicity of this novel variant. The C683R variant was engineered by site‐directed mutagenesis. NaV1.5/wild type (WT) and NaV1.5/C683R were expressed in tsA201 cells. Electrophysiological characterization of C683R was performed using the whole‐cell patch‐clamp technique. Adrenergic stimulation was mimicked by exposure to the protein kinase A activator 8‐CPT‐cAMP. The impact of β‐blockers was tested by exposing NaV1.5/WT and NaV1.5/C683R currents to propranolol and nadolol. C683R resulted in a co‐association of gain‐of‐function and loss‐of‐function properties of NaV1.5. Gain‐of‐function properties were characterized by a significant increase of the maximal NaV1.5 current density compared with NaV1.5/WT (861 ± 309 vs. 627 ± 489 pA/pF; P < 0.05, n ≥ 9) that was potentiated in NaV1.5/C683R with 8‐CPT‐cAMP stimulation (869 ± 287 vs. 607 ± 320 pA/pF; P < 0.05, n ≥ 12). C683R also resulted in a significant hyperpolarizing shift in the voltage of steady‐state activation (−65.4 ± 3.0 vs. −57.2 ± 4.8 mV; P < 0.001), resulting in an increased window current compared with WT. The loss‐of‐function effect of NaV1.5/C683R was characterized by significantly increased closed‐state inactivation compared with NaV1.5/WT (P < 0.05). C683R is a novel SCN5A variant resulting in a co‐association of gain‐of‐function and loss‐of‐function properties of the cardiac sodium channel NaV1.5. The phenotype is characterized by adrenaline‐triggered ventricular arrhythmias. Electrophysiological properties and clinical manifestations are different from long‐QT‐3 or Brugada syndrome and might represent a distinct inherited arrhythmia syndrome.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".