SCN5A

Chr 3ARAD

sodium voltage-gated channel alpha subunit 5

Also known as: CDCD2, CMD1E, CMPD2, HB1, HB2, HBBD, HH1, ICCD

The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

Primary Disease Associations & Inheritance

{Sudden infant death syndrome, susceptibility to}MIM #272120

Atrial fibrillation, familial, 10MIM #614022

Brugada syndrome 1MIM #601144

Cardiomyopathy, dilated, 1EMIM #601154

Heart block, nonprogressiveMIM #113900

Heart block, progressive, type IAMIM #113900

Long QT syndrome 3MIM #603830

Sick sinus syndrome 1MIM #608567

Ventricular fibrillation, familial, 1MIM #603829

UniProtProgressive familial heart block 1A

UniProtFamilial paroxysmal ventricular fibrillation 1

UniProtAtrial standstill 1

Active trials

Pathogenic / LP

439

ClinVar variants

Pubs (1 yr)

2.8

Missense Z

0.31

LOEUF· LoF intolerant

Clinical Summary— SCN5A

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Gene-Disease Validity (ClinGen)

arrhythmogenic right ventricular cardiomyopathy · ADLimited

Limited evidence — not for standalone diagnostic reporting

4 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

51 Pathogenic / Likely Pathogenic· 270 VUS of 439 total submissions

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GeneReview available — SCN5A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

ensembl: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.31LOEUF

pLI 0.913

Z-score 6.70

OE 0.21 (0.14–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.75Z-score

OE missense 0.78 (0.74–0.82)

967 obs / 1239.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.21 (0.14–0.31)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.74–0.82)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98

0≤1.21.6

LoF obs/exp: 17 / 82.8Missense obs/exp: 967 / 1239.5Syn Z: 0.34

0.6744th %ile

GOF

0.81top 10%

LOF

0.3842th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 49% of P/LP variants are LoF · LOEUF 0.31

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn co-expression experiments, L325R channels interfered with the proper function of WT channels, suggesting that a dominant negative phenomenon may underlie BrS triggered by fever.PMID:15890323

GOFA heterozygous deletion mutation in the cardiac sodium channel gene SCN5A with loss- and gain-of-function characteristics manifests as isolated conduction disease, without signs of Brugada or long QT syndrome.PMID:23840796

LOFThey also demonstrate that haploinsufficiency of SCN5A is associated with increased accumulation of reactive oxygen species (ROS) in a genetically engineered murine model.PMID:29457788

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

439 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30

Likely Pathogenic21

VUS270

Likely Benign115

Conflicting3

Pathogenic

Likely Pathogenic

270

VUS

115

Likely Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	0	15	0	30
Likely Pathogenic	10	6	5	0	21
VUS	5	238	22	5	270
Likely Benign	0	4	42	69	115
Benign	0	0	0	0	0
Conflicting	—				3
Total	30	248	84	74	439

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SCN5A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SCN5A-related long QT syndrome

definitive

ADGain Of FunctionAltered Gene Product Structure

Cardiac

G2P ↗

missense variantinframe deletioninframe insertion

SCN5A-related Brugada syndrome

definitive

ADLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level

Cardiac

G2P ↗

splice region variantsplice acceptor variantsplice donor variantframeshift variantstop gainedmissense variantinframe deletioninframe insertionstop gained NMD triggeringframeshift variant NMD triggering

SCN5A-related arrhythmogenic right ventricular cardiomyopathy

limited

ADUndeterminedUncertain

Cardiac

G2P ↗

SCN5A-related dilated cardiomyopathy

definitive

ADUndeterminedAltered Gene Product Structure, Decreased Gene Product Level

Cardiac

G2P ↗

missense variantstop gained NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org