Variant detail

SCN5AS524Y

c.1570Y · residue 524 · S → Y

Technical Plain language

HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS

NM_000335.5(SCN5A):c.1570Y (S524Y)

HGVSc

c.1570Y

cDNA change

c.1570Y

RefSeq transcript

NM_000335.5

Ensembl transcript

ENST00000333535.9

Protein HGVS

S524Y

Genomic coordinate

Chr3 38645523

ClinVar annotation

Not annotated in local ClinVar field

BrS1 penetrance Low risk

0% 90% credible interval 0–0%

0%20%50%100%

Well-established · n=1169 0 observed BrS1 carriers · 2.14 hypothetical affected and 7.86 hypothetical unaffected

LQT3 penetrance Low risk

0% 90% credible interval 0–0%

0%20%50%100%

Well-established · n=1169 0 observed LQT3 carriers · 0.154 hypothetical affected and 4.85 hypothetical unaffected

One-sentence summary

Roughly fewer than 1 in 100 people who carry S524Y are estimated to eventually be diagnosed with Brugada syndrome — low penetrance, with well-supported evidence from 1169 carriers. The residue lies in a Mild_Hotspot region for BrS1 and a Non_Hotspot region for LQT3.

Executive summary

Sources used for interpretation

The BrS1 and LQT3 penetrance estimates combine observed carrier counts with phenotype-specific feature-based model starting points. Other rows summarize supporting annotations for interpretation; not every row is a direct input to the model.

Estimatemodel output Observedmeasured in people/assays Model inputassumed, not observed Predictedcomputational Externalthird-party

EstimateModel-based penetrance estimatesBrS1 0% · LQT3 0%

Model inputHypothetical observationsBrS1 2.14/7.86 · LQT3 0.154/4.85

ObservedObserved carriers (literature + cohorts)1169 · Well-established

ObservedPopulation observations (gnomAD v4)1150 alleles

PredictedIn silico predictorsREVEL · PolyPhen-2 · PROVEAN · BLAST-PSSM

ObservedFunctional / electrophysiologyNormal

PredictedStructural contextMild_Hotspot

ExternalClinVar classificationNot annotated

ExternalAutomated ACMG reviewNot a classification

ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed

1169

0 BrS1 · 0 LQT3 · 1169 unaffected

Model prior: BrS1 2.14 hypothetical affected / 7.86 hypothetical unaffected; LQT3 0.154 hypothetical affected / 4.85 hypothetical unaffected

Well-established

Functional data

Normal

8 published electrophysiology studies

Predictors and density

REVEL —range 0-1

PolyPhen-2 Probably damaging0.959range 0-1

BrS1 density Sparse region0.291range 0-1

LQT3 density Sparse region0.025range 0-1

PROVEAN Deleterious-2.55cutoff <= -2.5

BLAST-PSSM -1.03lower = less tolerated

Range labels show the expected scale or cutoff. Calls are rough orientation from published cutoffs (hover a row) — not a clinical classification.

Automated ACMG/AMP review prompts

Generated from available data — not a clinical classification

PS3met · strong

Functional studies show damaging effect

PM1review

Hotspot or high BrS1/LQT3 density

PM2not met

Absent / extremely rare in population databases

PP3not met

Multiple computational predictors support deleterious

BS1met · strong

Allele frequency too high for disorder

BP4met · supporting

Computational predictors suggest no impact

Reported carrier data

Paper / cohort	Carriers	LQT3 / BrS1	Unaffected	Other observations	Variant context
PMID 16453024 Year 2006 · clinical carrier record	3	0 LQT3	1	2 other phenotype SIDS	Variant S524Y Residue 524 Curated carrier-count row
PMID 23571586 Year 2013 · clinical carrier record	1	0 LQT3	0	1 other phenotype stillbirth, SUDS	Variant S524Y Residue 524 Curated carrier-count row
PMID 20129283 Year 2010 · clinical carrier record	18	0 LQT3	18	Not separately annotated	Variant S524Y Residue 524 Curated carrier-count row
gnomAD population observations (v4)	1150	0 LQT3 0 BrS1	1150	Population observations; not known affected cases.	gnomAD v4 allele count.
Hypothetical observations from model prior (not observed patients)	5 LQT3 prior; 10 BrS1 prior	0.154 hypothetical LQT3 affected; 2.14 hypothetical BrS1 affected	4.85 hypothetical LQT3 unaffected; 7.86 hypothetical BrS1 unaffected	Phenotype-specific feature-based pseudo-counts added before observed carriers.	Model input; not literature or gnomAD evidence.
Combined literature, cohort, and gnomAD	1169	0 LQT3 0 BrS1	1169	Combined totals used in the dual penetrance estimates.	Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 2.14 hypothetical affected and 7.86 hypothetical unaffected observations; the LQT3 model starts with 0.154 hypothetical affected and 4.85 hypothetical unaffected observations. Each then updates that starting point with the real carrier counts above. As observed carrier counts grow, these feature-based starting points have less influence.

Functional studies · researcher detail

PMID	Year	Cell	Peak (%WT)	V½ act (mV)	V½ inact (mV)	Late (%WT)
15992732	2005	HEK	84	-1	-2	—
17331104	2007	HEK	1	-5	1.6	—
15851227	2004		—	—	—	—
15898185	2004		—	—	—	—
16453024	2006		—	—	—	—
23571586	2013		—	—	—	—
15992733	2005		—	—	—	—
20129283	2010		—	—	—	—

Structural neighbours · researcher detail

Residues within 15 Å of S524Y; observed variants link to their detail pages.

Neighbour	Distance (Å)	Observed variants
509	14.7
510	14.2
511	13.7
512	13.2	T512I,
513	12.6	R513C, c.1537delC, R513H, R513P,
514	12.0	G514C,
515	11.4
516	10.7
517	10.1	R517S, R517S,
518	9.3
519	8.5	S519F,
520	7.6	M520V, M520R,
521	6.6	K521E, c.1562delA,
522	5.4	P522S,
523	3.8	R523S, R523C, R523H,
524	0.0	c.1570_1571insG, S524Y,
525	3.8	S525G,
526	5.4	R526C, R526H,
527	6.6	G527R, G527R,
528	7.6	S528R, S528R, S528R,
529	8.5
530	9.3	F530V, F530S,
531	10.1	T531A, T531I,
532	10.7	F532L, F532C, F532L, F532L,
533	11.4	R533S, R533C, R533H,
534	12.0
535	12.6	R535G, R535X, R535Q,
536	13.2	D536H,
537	13.7
538	14.2	G538D
539	14.7

View this variant elsewhere

ClinVar → gnomAD → UniProt →