SCN5A

Chr 3ARAD

sodium voltage-gated channel alpha subunit 5

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

NCBI Gene: 6331 ENSG00000183873 UniProt: Q14524 OMIM: 600163

The encoded protein forms the pore-forming subunit of Nav1.5, a voltage-gated sodium channel that mediates the depolarizing phase of action potentials in cardiac myocytes and is responsible for the initial upstroke of the cardiac action potential that initiates the heartbeat. Mutations cause a spectrum of autosomal dominant cardiac arrhythmias and cardiomyopathies including long QT syndrome type 3, Brugada syndrome, dilated cardiomyopathy, progressive and nonprogressive heart block, and sudden infant death syndrome. The gene is highly constrained against loss-of-function variants, reflecting its critical role in cardiac electrical conduction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 0.319 OMIM phenotypes

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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GeneReview available — SCN5A

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

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

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

LoF OE0.21 (0.14–0.31)

0≤0.351.4

Missense OE0.78 (0.74–0.82)

0≤0.61.4

Synonymous OE0.98

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSCN5A-related long QT syndromeGOFAD

definitiveSCN5A-related Brugada syndromeLOFAD

limitedSCN5A-related arrhythmogenic right ventricular cardiomyopathyOTHERAD

definitiveSCN5A-related dilated cardiomyopathyOTHERAD

0.6744th %ile

GOF

0.81top 10%

LOF

0.3842th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOF1 literature citation · LOEUF 0.31

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.