Variant detail

SCN5AL409R

c.1226T>G · residue 409 · L → R
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000335.5(SCN5A):c.1226T>G (L409R)
HGVSc
c.1226T>G
cDNA change
c.1226T>G
RefSeq transcript
NM_000335.5
Ensembl transcript
ENST00000333535.9
Protein HGVS
L409R
Genomic coordinate
NC_000003.12:g.38647554A>C
ClinVar annotation
Not annotated in local ClinVar field
BrS1 penetrance Low risk
11% 90% credible interval 1–30%
0%20%50%100%

Limited evidence · n=0 0 observed BrS1 carriers · 1.09 hypothetical affected and 8.91 hypothetical unaffected

LQT3 penetrance High risk
60% 90% credible interval 25–90%
0%20%50%100%

Limited evidence · n=0 0 observed LQT3 carriers · 3 hypothetical affected and 2 hypothetical unaffected

One-sentence summary

Roughly 6 in 10 people who carry L409R are estimated to eventually be diagnosed with Long QT type 3 — high penetrance, though evidence is limited (0 carriers). The residue lies in a Non_Hotspot region for BrS1 and a 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 11% · LQT3 60%
Model inputHypothetical observationsBrS1 1.09/8.91 · LQT3 3/2
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
0 BrS1 · 0 LQT3 · 0 unaffected
Model prior: BrS1 1.09 hypothetical affected / 8.91 hypothetical unaffected; LQT3 3 hypothetical affected / 2 hypothetical unaffected
Limited evidence
Functional data
NA
No published electrophysiology
Predictors and density
REVEL Likely damaging0.995range 0-1
PolyPhen-2 NArange 0-1
BrS1 density Sparse region0.0434range 0-1
LQT3 density Hotspot region0.812range 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		 3 hypothetical LQT3 affected;
1.09 hypothetical BrS1 affected		 2 hypothetical LQT3 unaffected;
8.91 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 1.09 hypothetical affected and 8.91 hypothetical unaffected observations; the LQT3 model starts with 3 hypothetical affected and 2 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 L409R; observed variants link to their detail pages.

NeighbourDistance (Å)Observed variants
40312.0
4149.2 M414V,
9399.9 L939F,
4049.9 L404V, L404Q,
93712.1
177311.2
176511.2
84214.8
24912.3 K249X,
24712.8 V247L, V247L,
165314.7
25413.6
17718.6 I1771T,
40111.9 S401P,
177714.9 V1777M, V1777L, V1777L,
41814.3 E418K,
92612.4
176413.2 c.5290delG, V1764F,
37114.8 Q371E,
25010.5
4090.0 L409V, L409P,
9288.2 L928P,
92514.1 I925F,
165013.2 L1650F,
41712.4
93411.0
9338.5
147114.1
2469.9
9356.7 L935P,
177913.6 T1779M
4125.3 V412D,
92412.5 V924I,
147010.2
146414.4 c.4389_4396delCCTCTTTA, L1464P,
92710.2 N927S, N927K, N927K,
14669.5 c.4396_4397insG,
24514.3 Q245K,
177611.2
36913.8 M369K,
176712.2 Y1767C,
17699.6
40212.3 F402L, F402L, F402L,
176614.6 M1766L, M1766V, M1766L, M1766T,
41510.2 A415T,
164914.0 A1649V,
17687.5 I1768V,
94013.4 S940N,
177412.9 N1774D, c.5321_5324dupACTT,
147314.7 F1473S, F1473C,
146814.8 V1468F, V1468A,
4056.8
93811.7
93010.6 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
145914.3 c.4376_4379delTCTT,
17726.3 L1772V,
4104.3 A410V,
24212.8 A242D,
177012.1 I1770V,
9298.8
41611.0 Y416C,
4136.1 A413T, A413E,
4085.4
25311.8
146214.7
4077.0
9367.8
146711.3
17759.3 F1775V, p.F1775LfsX15,
37013.9 T370M,
92314.1
146913.2 I1469V,
4065.4 N406S, N406K, N406K,
4116.5 V411M,
24313.1
9324.7
25714.5
40013.8 G400R, G400R, G400E, G400A,
9319.7
164612.8
146311.0 N1463Y,
View this variant elsewhere
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