rs28937317 — SCN5A N1325S

Rare gain-of-function missense variant in the cardiac sodium channel Nav1.5 causing Long QT syndrome type 3 through persistent late sodium current and prolonged ventricular repolarization

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SCN5A N1325S — When the Heart's Electrical Off-Switch Stays On

Every heartbeat begins with a precisely timed electrical impulse. Millions of sodium channels along heart muscle membranes snap open, flood the cell with sodium ions, and trigger the rapid depolarization that generates a contraction. Then — just as critically — they close. The cardiac sodium channel Nav1.511 Nav1.5
The protein encoded by SCN5A; "Na" = sodium, "v" = voltage-gated, "1.5" = the cardiac isoform. Nav1.5 is responsible for the fast inward sodium current that initiates the cardiac action potential must inactivate completely within milliseconds to allow the cell to repolarize and prepare for the next beat.

The N1325S variant (ClinVar VCV000009370, Pathogenic/Likely pathogenic, 4-star review status, multiple submitters without conflicts) disrupts this inactivation. Instead of fully closing, mutant Nav1.5 channels continue to leak a small but persistent current — the "late sodium current" — long into the repolarization phase. The electrical result is a prolonged QT interval on the ECG and the substrate for lethal cardiac arrhythmias. The clinical diagnosis is Long QT syndrome type 322 Long QT syndrome type 3
LQT3 is one of approximately 17 genetic subtypes of LQTS; it is specifically caused by gain-of-function variants in SCN5A and accounts for roughly 8-10% of all genotype-positive LQTS cases.

The Mechanism

The asparagine-to-serine substitution at position 1324 (MANE Select transcript NM_000335.5) sits in the Domain III-IV linker region33 Domain III-IV linker region
The cytoplasmic loop connecting transmembrane domains III and IV of Nav1.5; this region acts as the inactivation particle — it physically plugs the channel pore after opening. Mutations here are a common mechanism for gain-of-function channel defects of Nav1.5. Disrupting the asparagine residue impairs the fast inactivation gate, allowing channels to flicker between conducting and partially inactivated states. The result is a persistent inward sodium current (I_NaL) that outlasts the normal channel-open window by tens to hundreds of milliseconds.

Excess late sodium entry has two critical downstream consequences. First, it directly prolongs the action potential duration (APD), manifesting as a prolonged QTc interval44 prolonged QTc interval
QTc = QT interval corrected for heart rate. Normal upper limit: 440 ms in men, 460 ms in women. Each 10-ms increase above baseline in LQT3 patients is associated with a 19% increase in cardiac event risk on the surface ECG. Second, the persistent sodium influx secondarily activates CaMKII55 CaMKII
Calmodulin-dependent protein kinase II — a calcium/sodium-sensitive kinase that, when chronically activated, phosphorylates ryanodine receptors and other calcium-handling proteins, promoting calcium overload and arrhythmogenic spontaneous depolarizations. This creates a pathological feedback loop where Nav1.5 dysfunction feeds into calcium dysregulation, multiplying arrhythmia risk.

The N1325S variant is classified as a gain-of-function66 gain-of-function
Unlike loss-of-function SCN5A variants that cause Brugada syndrome by reducing peak sodium current, N1325S increases total sodium entry through the persistent late current. This distinction matters for drug selection: sodium channel blockers that suppress late current (mexiletine, ranolazine) are therapeutic; those that indiscriminately block all sodium current (Class I antiarrhythmics like flecainide in high doses) require careful dosing variant — the mechanistic opposite of Brugada syndrome SCN5A variants.

The Evidence

Tian et al., 200477 Tian et al., 2004
Tian XL et al. Cardiovascular Research 2004 — transgenic mice homozygous for N1325S had action potential duration at 90% repolarization of 69 ± 5.9 ms versus 46.7 ± 4.8 ms in controls; 52 of 156 transgenic mice died from spontaneous arrhythmia during the study established the in vivo pathogenicity of N1325S using transgenic mice, demonstrating spontaneous polymorphic ventricular tachycardia and fibrillation frequently causing sudden cardiac death. Mexiletine treatment in these mice suppressed arrhythmias and normalized action potential duration — the first evidence that this variant is pharmacologically targetable.

The largest clinical study of LQT3 patients comes from Wilde et al., 201688 Wilde et al., 2016
Wilde AAM et al. Circulation 2016 — 406 LQT3 patients with 51 distinct SCN5A mutations; 391 analyzed for outcomes; mean follow-up not stated but multicenter international registry over decades, an international multicenter registry of 391 LQT3 patients: 30% experienced cardiac events (syncope, aborted arrest, or sudden death); 20% had life-threatening events. Every 10-ms increase in QTc above baseline was associated with a 19% increase in cardiac events. Beta-blocker therapy reduced events by 83% in women but showed no clear benefit in men — a sex-specific drug response that carries direct management implications.

For treatment, Mazzanti et al., 201699 Mazzanti et al., 2016
Mazzanti A et al. JACC 2016 — 34 LQT3 patients, 56% male, median age 22 years, treated with mexiletine at 8 mg/kg/day; median follow-up 36 months; the reduction in event rates was highly statistically significant (p=0.0097 for annual rate) provided the strongest clinical evidence for gene-specific mexiletine therapy in LQT3. Mexiletine shortened QTc by a mean of 63 ms and reduced annual arrhythmic event rates from 10.3% to 0.7%. For patients who cannot tolerate mexiletine, van den Berg et al., 20141010 van den Berg et al., 2014
van den Berg MP et al. Int J Cardiol 2014 — single case report of N1325S patient successfully managed with ranolazine + beta-blocker after inadequate response to beta-blocker alone; ranolazine is a late sodium current inhibitor with a more favorable side-effect profile for some patients documented successful management with ranolazine plus beta-blocker in a confirmed N1325S carrier.

Li et al., 20201111 Li et al., 2020
Li G et al. Front Pharmacol 2020 — N1325S and R1623Q were identified as mexiletine-sensitive mutations based on their gating properties; M1652R was not; the study explains why not all LQT3 variants respond equally to mexiletine specifically confirmed N1325S as a mexiletine-sensitive mutation at the biophysical level, demonstrating that its gating properties (particularly window current expansion) predict a favorable clinical drug response — providing a mechanistic rationale for gene-specific therapy.

Practical Actions

LQT3 caused by N1325S requires cardiological management. Three priorities dominate: (1) quantify the QTc interval and arrhythmia burden at baseline; (2) initiate gene-specific pharmacotherapy with mexiletine, which specifically targets the mechanism of this variant; (3) assess ICD candidacy for high-risk individuals. QT-prolonging drugs — including many common antibiotics, antipsychotics, and antidepressants — must be reviewed and substituted where possible.

LQT3 arrhythmias characteristically occur at slower heart rates and during sleep or rest, unlike LQT1 (exercise-triggered) or LQT2 (auditory/startle- triggered). This has practical implications: the risk period is not exercise but rather nocturnal bradycardia. Avoiding fever (which accelerates sodium channel dysfunction) and certain medications is also critical.

Interactions

N1325S interacts with the broader SCN5A channelopathy landscape. Other pathogenic SCN5A gain-of-function variants cause LQT3 through the same mechanism — all produce late sodium current — but vary in their mexiletine sensitivity based on gating kinetics. Loss-of-function SCN5A variants (rs45620037 and related Brugada syndrome variants) cause the mechanistic opposite phenotype; compound heterozygosity for gain- and loss-of-function SCN5A variants can produce overlap syndromes with both prolonged QT and Brugada-pattern ECG changes. Other inherited arrhythmia genes — KCNQ1 (LQT1), KCNH2 (LQT2), KCNE1, KCNE2 — can compound QT prolongation risk when co-inherited with SCN5A variants.

Drug Interactions

mexiletine dose_adjustment literature
ranolazine dose_adjustment literature
flecainide dose_adjustment literature
sotalol increased_toxicity literature
amiodarone dose_adjustment literature
erythromycin increased_toxicity FDA
clarithromycin increased_toxicity FDA
haloperidol increased_toxicity FDA
methadone increased_toxicity FDA
cisapride contraindicated FDA

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Nav1.5 Normal

No SCN5A N1325S mutation — no LQT3 risk from this variant

You carry two copies of the normal SCN5A allele at this position and do not have the N1325S mutation. Your Nav1.5 cardiac sodium channel inactivates normally at this site, and you are not at elevated risk for Long QT syndrome type 3 from this specific variant. Virtually everyone in the population shares this result — N1325S is absent or near-absent from all population databases (gnomAD exomes: C allele frequency 0.0000021 globally), consistent with strong negative selection against a disease-causing variant. Other inherited cardiac arrhythmia variants in SCN5A and other arrhythmia genes are not captured by this result.

CT N1325S Carrier High Risk

Carries one copy of SCN5A N1325S — pathogenic for Long QT syndrome type 3

The pathogenic mechanism of N1325S is gain-of-function through impaired inactivation. Normal Nav1.5 opens briefly during the cardiac action potential upstroke, then closes within milliseconds via fast inactivation. N1325S disrupts the inactivation gate at the Domain III-IV linker, causing channels to flicker between conducting and inactivated states throughout the action potential plateau. The resulting persistent inward current (I_NaL) delays repolarization, stretching the QT interval and creating the electrical substrate for early afterdepolarizations (EADs) and torsades de pointes — a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and sudden death.

LQT3 has a characteristic clinical phenotype distinct from LQT1 and LQT2: - Triggers: events occur predominantly at rest, during sleep, or with bradycardia — not with exercise or acoustic startle - QTc: often markedly prolonged; higher QTc values confer greater risk - Sex: males with LQT3 appear to have higher event rates than females (reversed compared to LQT1/LQT2); beta-blocker protection is predominantly seen in females - Drug response: mexiletine is specifically effective for LQT3 because it preferentially blocks late sodium current (the mechanism of N1325S) versus peak current; QTc shortening of ≥40 ms predicts good response

N1325S specifically has been characterized as a mexiletine-sensitive mutation based on its gating properties: expanded window current with increased late sodium current that responds well to mexiletine-class sodium channel blockers.

QT-prolonging drugs are particularly dangerous in LQT3 carriers. The FDA maintains a list of medications with known QT-prolonging risk. Key categories to avoid or manage carefully: macrolide antibiotics (erythromycin, clarithromycin), fluoroquinolones, antipsychotics, tricyclic antidepressants, methadone, and Class IA/III antiarrhythmics.

CC Homozygous N1325S Homozygous

Carries two copies of SCN5A N1325S — severely elevated LQT3 risk, extremely rare

You carry two copies of the SCN5A N1325S pathogenic variant, one on each chromosome 3. This is an exceptionally rare genotype — the C allele is present at a frequency of approximately 0.000002 globally, making homozygosity biologically near-impossible in the general population and virtually unreported in the published literature. In the N1325S transgenic mouse model, homozygous animals exhibited more severe prolongation of action potential duration and higher rates of sudden arrhythmic death than heterozygous mice. All cardiac sodium channels would be impaired, with no wild-type Nav1.5 to compensate. The clinical management priorities are the same as for CT heterozygotes but with higher urgency — immediate referral to an inherited arrhythmia center is required.