Variant detail

SCN5AA1680T

c.5038G>A · residue 1680 · A → T

Technical Plain language

HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS

NM_000335.5(SCN5A):c.5038G>A (A1680T)

HGVSc

c.5038G>A

cDNA change

c.5038G>A

RefSeq transcript

NM_000335.5

Ensembl transcript

ENST00000333535.9

Protein HGVS

A1680T

Genomic coordinate

NC_000003.12:g.38592825C>T

ClinVar annotation

Not annotated in local ClinVar field

BrS1 penetrance Moderate risk

20% 90% credible interval 9–34%

0%20%50%100%

Emerging evidence · n=18 4 observed BrS1 carriers · 1.69 hypothetical affected and 8.31 hypothetical unaffected

LQT3 penetrance Low risk

5% 90% credible interval 0–13%

0%20%50%100%

Emerging evidence · n=18 1 observed LQT3 carriers · 0.0513 hypothetical affected and 4.95 hypothetical unaffected

One-sentence summary

Roughly 1 in 4 people who carry A1680T are estimated to eventually be diagnosed with Brugada syndrome — moderate penetrance, though evidence is limited (18 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 20% · LQT3 5%

Model inputHypothetical observationsBrS1 1.69/8.31 · LQT3 0.0513/4.95

ObservedObserved carriers (literature + cohorts)18 · Emerging evidence

ObservedPopulation observations (gnomAD v4)13 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

4 BrS1 · 1 LQT3 · 13 unaffected

Model prior: BrS1 1.69 hypothetical affected / 8.31 hypothetical unaffected; LQT3 0.0513 hypothetical affected / 4.95 hypothetical unaffected

Emerging evidence

Functional data

Normal

9 published electrophysiology studies

Predictors and density

REVEL Likely damaging0.889range 0-1

PolyPhen-2 Probably damaging1range 0-1

BrS1 density Sparse region0.177range 0-1

LQT3 density Sparse region0.0199range 0-1

PROVEAN Deleterious-3.44cutoff <= -2.5

BLAST-PSSM -3.34lower = 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 16712702 Year 2006 · clinical carrier record	1	0 LQT3	0	1 other phenotype Sudden adult death syndrome	Variant A1680T Residue 1680 Curated carrier-count row
PMID 18508782 Year 2008 · clinical carrier record	2	0 LQT3 1 BrS1	0	1 other phenotype SD	Variant A1680T Residue 1680 Curated carrier-count row
PMID 19564561 Year 2009 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant A1680T Residue 1680 Curated carrier-count row
PMID 23631430 Year 2013 · clinical carrier record	1	1 LQT3	0	Not separately annotated	Variant A1680T Residue 1680 Curated carrier-count row
PMID 26746457 Year 2016 · clinical carrier record	1	0 LQT3	0	1 other phenotype AF, BBB	Variant A1680T Residue 1680 Curated carrier-count row
PMID 20129283 Year 2010 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant A1680T Residue 1680 Curated carrier-count row
PMID 20129283 Year 2010 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant A1680T Residue 1680 Curated carrier-count row
PMID 30254039 Year 2018 · clinical carrier record	1	0 LQT3 1 BrS1	0	Not separately annotated	Variant A1680T Residue 1680 Curated carrier-count row
gnomAD population observations (v4)	13	0 LQT3 0 BrS1	13	Population observations; not known affected cases.	gnomAD v4 allele count.
Hypothetical observations from model prior (not observed patients)	5 LQT3 prior; 10 BrS1 prior	0.0513 hypothetical LQT3 affected; 1.69 hypothetical BrS1 affected	4.95 hypothetical LQT3 unaffected; 8.31 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	18	1 LQT3 4 BrS1	13	Combined totals used in the dual penetrance estimates.	Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 1.69 hypothetical affected and 8.31 hypothetical unaffected observations; the LQT3 model starts with 0.0513 hypothetical affected and 4.95 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)
16712702	2006		—	—	—	—
18508782	2008		—	—	—	—
19564561	2009		—	—	—	—
23631430	2013		—	—	—	—
26746457	2016		—	—	—	—
20129283	2010		—	—	—	—
20129283	2010		—	—	—	—
30254039	2018		—	—	—	—
32533946	2020	HEK	90	-5.3	-1.2	—

Structural neighbours · researcher detail

Residues within 15 Å of A1680T; observed variants link to their detail pages.

Neighbour	Distance (Å)	Observed variants
1741	7.8	D1741N, D1741Y, D1741E, D1741E,
1304	14.9	T1304M,
1687	14.7
1698	13.8	A1698T,
1745	13.5
1673	11.9
1675	8.0
1743	8.7	G1743R, G1743R, G1743E,
1681	4.5	c.5040_5042delTTAinsC, Y1681F,
1694	6.8
1226	8.1
1747	11.7	V1747M,
1716	13.7	p.L1716SfsX71,
1695	6.0	Q1695X,
1688	11.3
1684	12.2	W1684R, W1684R,
1676	7.0	M1676T, M1676I, M1676I, M1676I,
1692	14.1
1744	9.7	S1744I,
1721	13.7
1672	11.5	S1672Y,
1742	9.2
1693	8.5
1699	11.7
1738	12.9	S1738T, S1738F,
1680	0.0	A1680T, A1680P,
1703	13.2
1719	11.8
1731	13.6
1228	11.8	Y1228H, Y1228C, Y1228F,
1690	12.0	c.5068_5070delGA, D1690N,
1678	7.3	N1678S,
1223	14.5	c.3667delG,
1697	13.5
1230	13.9	E1230K,
1227	7.0
1300	12.5
1674	11.7	F1674V,
1229	12.6
1748	12.9	p.G1748del, G1748D
1683	9.4
1301	12.5
1696	9.9
1689	14.6	D1689N,
1739	10.7	R1739W, R1739Q,
1700	11.2
1717	15.0	L1717P,
1734	14.1
1751	13.0
1677	6.7
1682	5.2
1752	14.9
1722	14.5	N1722D,
1740	6.9	G1740R, G1740R,
1225	11.9	E1225K, G1225K,
1691	14.6
1720	10.1	c.5157delC,
1732	11.3
1679	5.6
1685	13.7

View this variant elsewhere

ClinVar → gnomAD → UniProt →