Variant detail

SCN5AG1319V

c.3956G>T · residue 1319 · G → V

Technical Plain language

HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS

NM_000335.5(SCN5A):c.3956G>T (G1319V)

HGVSc

c.3956G>T

cDNA change

c.3956G>T

RefSeq transcript

NM_000335.5

Ensembl transcript

ENST00000333535.9

Protein HGVS

G1319V

Genomic coordinate

NC_000003.12:g.38603913C>A

ClinVar annotation

Not annotated in local ClinVar field

BrS1 penetrance Moderate risk

31% 90% credible interval 18–47%

0%20%50%100%

Emerging evidence · n=17 6 observed BrS1 carriers · 2.47 hypothetical affected and 7.53 hypothetical unaffected

LQT3 penetrance Low risk

2% 90% credible interval 0–7%

0%20%50%100%

Emerging evidence · n=17 0 observed LQT3 carriers · 0.364 hypothetical affected and 4.64 hypothetical unaffected

One-sentence summary

Roughly 1 in 3 people who carry G1319V are estimated to eventually be diagnosed with Brugada syndrome — moderate penetrance, though evidence is limited (17 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 31% · LQT3 2%

Model inputHypothetical observationsBrS1 2.47/7.53 · LQT3 0.364/4.64

ObservedObserved carriers (literature + cohorts)17 · Emerging evidence

ObservedPopulation observations (gnomAD v4)11 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

6 BrS1 · 0 LQT3 · 11 unaffected

Model prior: BrS1 2.47 hypothetical affected / 7.53 hypothetical unaffected; LQT3 0.364 hypothetical affected / 4.64 hypothetical unaffected

Emerging evidence

Functional data

Normal

13 published electrophysiology studies

Predictors and density

REVEL Likely damaging0.967range 0-1

PolyPhen-2 Probably damaging1range 0-1

BrS1 density Sparse region0.286range 0-1

LQT3 density Sparse region0.0518range 0-1

PROVEAN Deleterious-7.96cutoff <= -2.5

BLAST-PSSM -5.28lower = 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

PP3met · supporting

Multiple computational predictors support deleterious

BS1not met

Allele frequency too high for disorder

BP4not met

Computational predictors suggest no impact

Reported carrier data

Paper / cohort	Carriers	LQT3 / BrS1	Unaffected	Other observations	Variant context
PMID 12106943 Year 2002 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 19843921 Year 2009 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 21273195 Year 2011 · clinical carrier record	3	0 LQT3 3 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 22885917 Year 2012 · clinical carrier record	2	0 LQT3 2 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 25179549 Year 2014 · clinical carrier record	2	0 LQT3	0	2 other phenotype DCM	Variant G1319V Residue 1319 Curated carrier-count row
PMID 17854786 Year 2007 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 19251209 Year 2009 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 20129283 Year 2010 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 20129283 Year 2010 · clinical carrier record	3	0 LQT3 3 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 29325976 Year 2018 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 29759671 Year 2018 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
PMID 30059973 Year 2018 · clinical carrier record	8	8 LQT3	0	Not separately annotated	Variant G1319V Residue 1319 Curated carrier-count row
gnomAD population observations (v4)	11	0 LQT3 0 BrS1	11	Population observations; not known affected cases.	gnomAD v4 allele count.
Hypothetical observations from model prior (not observed patients)	5 LQT3 prior; 10 BrS1 prior	0.364 hypothetical LQT3 affected; 2.47 hypothetical BrS1 affected	4.64 hypothetical LQT3 unaffected; 7.53 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	17	0 LQT3 6 BrS1	11	Combined totals used in the dual penetrance estimates.	Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 2.47 hypothetical affected and 7.53 hypothetical unaffected observations; the LQT3 model starts with 0.364 hypothetical affected and 4.64 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)
24573164	2014	HEK	75	—	-1.92	—
12106943	2002		—	—	—	—
19843921	2009		—	—	—	—
21273195	2011		—	—	—	—
22885917	2012		—	—	—	—
25179549	2014		—	—	—	—
17854786	2007		—	—	—	—
19251209	2009		—	—	—	—
20129283	2010		—	—	—	—
20129283	2010		—	—	—	—
29325976	2018		—	—	—	—
29759671	2018		—	—	—	—
30059973	2018		—	—	—	—

Structural neighbours · researcher detail

Residues within 15 Å of G1319V; observed variants link to their detail pages.

Neighbour	Distance (Å)	Observed variants
1328	13.9	V1328M,
1659	5.4
1480	9.5	c.4437+5G>A, c.4438-1C>T,
1773	14.9
1653	11.1
1315	8.2
1771	15.0	I1771T,
1652	13.2	M1652T, M1652R,
1314	8.6	c.3940_3941delCT,
1320	4.2	M1320I, M1320I, M1320I,
1666	14.6
1656	6.3
1477	10.8	K1477N, K1477N,
1767	13.0	Y1767C,
1313	11.3
1660	9.1	I1660V, I1660S,
1654	11.9
1769	13.9
1316	10.5	R1316Q, R1316L,
1766	12.0	M1766L, M1766V, M1766L, M1766T,
1319	0.0	G1319V,
1774	13.5	N1774D, c.5321_5324dupACTT
1479	13.5
1473	11.3	F1473S, F1473C,
1663	10.9
1657	10.0
1662	9.8
1324	8.4
1481	13.5	G1481R, G1481R, G1481E, G1481V,
1317	5.2	F1317C,
1327	12.4
1318	4.4
1321	5.6	R1321K,
1323	6.2	V1323G,
1770	10.7	I1770V,
1322	5.2	c.3963+2T>C, c.3963+4A>G,
1312	12.3
1326	10.9	A1326S,
1763	13.9	V1763M, V1763L, V1763L,
1311	13.6	L1311P,
1476	10.5	Q1476X, Q1476R,
1661	11.2	G1661R, G1661R, G1661E,
1655	7.7
1325	9.5	N1325S,
1664	14.2
1658	10.0

View this variant elsewhere

ClinVar → gnomAD → UniProt →