Variant detail

SCN5AN420K

c.1260C>A · residue 420 · N → K

Technical Plain language

HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS

NM_000335.5(SCN5A):c.1260C>A (N420K)

HGVSc

c.1260C>A

cDNA change

c.1260C>A

RefSeq transcript

NM_000335.5

Ensembl transcript

ENST00000333535.9

Protein HGVS

N420K

Genomic coordinate

NC_000003.12:g.38647520G>T

ClinVar annotation

Not annotated in local ClinVar field

BrS1 penetrance Low risk

12% 90% credible interval 1–32%

0%20%50%100%

Limited evidence · n=0 0 observed BrS1 carriers · 1.22 hypothetical affected and 8.78 hypothetical unaffected

LQT3 penetrance Low risk

14% 90% credible interval 0–44%

0%20%50%100%

Limited evidence · n=0 0 observed LQT3 carriers · 0.706 hypothetical affected and 4.29 hypothetical unaffected

One-sentence summary

Roughly 1 in 7 people who carry N420K are estimated to eventually be diagnosed with Long QT type 3 — low penetrance, though evidence is limited (0 carriers). The residue lies in a Non_Hotspot region for BrS1 and a Mild_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 12% · LQT3 14%

Model inputHypothetical observationsBrS1 1.22/8.78 · LQT3 0.706/4.29

ObservedObserved carriers (literature + cohorts)0 · Limited evidence

ObservedPopulation observations (gnomAD v4)0 alleles

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

ObservedFunctional / electrophysiologyNA

PredictedStructural contextNon_Hotspot

ExternalClinVar classificationNot annotated

ExternalAutomated ACMG reviewNot a classification

ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed

0 BrS1 · 0 LQT3 · 0 unaffected

Model prior: BrS1 1.22 hypothetical affected / 8.78 hypothetical unaffected; LQT3 0.706 hypothetical affected / 4.29 hypothetical unaffected

Limited evidence

Functional data

No published electrophysiology

Predictors and density

REVEL Uncertain0.677range 0-1

PolyPhen-2 NArange 0-1

BrS1 density Sparse region0.0942range 0-1

LQT3 density Sparse region0.162range 0-1

PROVEAN NAcutoff <= -2.5

BLAST-PSSM NAlower = 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

PS3not met

Functional studies show damaging effect

PM1review

Hotspot or high BrS1/LQT3 density

PM2met · moderate

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
gnomAD population observations (v4)	0	0 LQT3 0 BrS1	0	Population observations; not known affected cases.	gnomAD v4 allele count.
Hypothetical observations from model prior (not observed patients)	5 LQT3 prior; 10 BrS1 prior	0.706 hypothetical LQT3 affected; 1.22 hypothetical BrS1 affected	4.29 hypothetical LQT3 unaffected; 8.78 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	0	0 LQT3 0 BrS1	0	Combined totals used in the dual penetrance estimates.	Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 1.22 hypothetical affected and 8.78 hypothetical unaffected observations; the LQT3 model starts with 0.706 hypothetical affected and 4.29 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.

Structural neighbours · researcher detail

Residues within 15 Å of N420K; observed variants link to their detail pages.

Neighbour	Distance (Å)	Observed variants
414	11.3	M414V,
939	11.3	L939F,
937	9.4
839	13.8	L839P,
842	13.0
943	12.8	S943N,
240	12.4	V240M,
418	7.5	E418K,
237	11.1
234	14.6	P234S,
417	5.0
934	14.1
933	11.2
246	13.3
935	14.4	L935P,
412	12.1	V412D,
245	12.5	Q245K,
244	14.3
415	8.6	A415T,
940	7.4	S940N,
420	0.0
938	12.9
241	10.5
235	10.8	c.703+1G>A, G235R, G235R, c.704-1G>C,
942	14.0
419	4.9	Q419X,
423	5.7
834	14.1	N834D,
837	12.8
239	9.5	I239V, I239V ,
1780	14.8	E1780G
242	9.4	A242D,
416	5.2	Y416C,
413	10.1	A413T, A413E,
841	12.8	p.N841TfsX2, N841K, N841K,
236	12.6
941	10.4	S941N, S941F,
936	9.7
238	6.5
838	10.3
422	6.4
421	5.2
411	14.5	V411M,
243	13.0
835	12.8	S835A, S835L,

View this variant elsewhere

ClinVar → gnomAD → UniProt →