Variant detail

SCN5AV411M

c.1231G>A · residue 411 · V → M
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000335.5(SCN5A):c.1231G>A (V411M)
HGVSc
c.1231G>A
cDNA change
c.1231G>A
RefSeq transcript
NM_000335.5
Ensembl transcript
ENST00000333535.9
Protein HGVS
V411M
Genomic coordinate
NC_000003.12:g.38647549C>T
ClinVar annotation
Not annotated in local ClinVar field
BrS1 penetrance Low risk
5% 90% credible interval 0–12%
0%20%50%100%

Emerging evidence · n=18 0 observed BrS1 carriers · 1.3 hypothetical affected and 8.7 hypothetical unaffected

LQT3 penetrance High risk
83% 90% credible interval 69–94%
0%20%50%100%

Emerging evidence · n=18 17 observed LQT3 carriers · 2.15 hypothetical affected and 2.85 hypothetical unaffected

One-sentence summary

Roughly 8 in 10 people who carry V411M are estimated to eventually be diagnosed with Long QT type 3 — high penetrance, though evidence is limited (18 carriers). The residue lies in a Mild_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 5% · LQT3 83%
Model inputHypothetical observationsBrS1 1.3/8.7 · LQT3 2.15/2.85
ObservedObserved carriers (literature + cohorts)18 · Emerging evidence
ObservedPopulation observations (gnomAD v4)0 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
18
0 BrS1 · 17 LQT3 · 1 unaffected
Model prior: BrS1 1.3 hypothetical affected / 8.7 hypothetical unaffected; LQT3 2.15 hypothetical affected / 2.85 hypothetical unaffected
Emerging evidence
Functional data
Normal
21 published electrophysiology studies
Predictors and density
REVEL Likely damaging0.947range 0-1
PolyPhen-2 Probably damaging1range 0-1
BrS1 density Sparse region0.128range 0-1
LQT3 density Hotspot region0.626range 0-1
PROVEAN Deleterious-2.94cutoff <= -2.5
BLAST-PSSM -1.73lower = 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
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
Year 2011 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2000 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2005 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2006 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2010 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2012 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2012 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2012 · clinical carrier record
4 4 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2013 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2014 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2016 · clinical carrier record
2 2 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2016 · clinical carrier record
1 0 LQT3 0 1 other phenotype
SD
Variant V411M
Residue 411
Curated carrier-count row
Year 2016 · clinical carrier record
6 5 LQT3 1 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2016 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2016 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2012 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2016 · clinical carrier record
7 7 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2009 · clinical carrier record
3 3 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
Year 2018 · clinical carrier record
10 10 LQT3 0 Not separately annotated
Variant V411M
Residue 411
Curated carrier-count row
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		 2.15 hypothetical LQT3 affected;
1.3 hypothetical BrS1 affected		 2.85 hypothetical LQT3 unaffected;
8.7 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 17 LQT3
0 BrS1		 1 Combined totals used in the dual penetrance estimates. Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 1.3 hypothetical affected and 8.7 hypothetical unaffected observations; the LQT3 model starts with 2.15 hypothetical affected and 2.85 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
PMIDYearCellPeak (%WT)V½ act (mV)V½ inact (mV)Late (%WT)
21193062 2011HEK 100-8.1-7.92
10961955 2000 ————
15840476 2005 ————
16712702 2006 ————
20541041 2010 ————
22360817 2012 ————
22885918 2012 ————
23098067 2012 ————
23631430 2013 ————
24606995 2014 ————
26496715 2016 ————
26498160 2016 ————
26669661 2016 ————
26940925 2016 ————
27485560 2016 ————
29017927 2017 ————
22721569 2012 ————
26888838 2015 ————
27566755 2016 ————
19716085 2009 ————
30059973 2018 ————
Structural neighbours · researcher detail

Residues within 15 Å of V411M; observed variants link to their detail pages.

NeighbourDistance (Å)Observed variants
40314.0
4144.8 M414V,
93913.4 L939F,
164311.7 I1643L,
40410.9 L404V, L404Q,
93714.8
177812.1
177312.9
2496.0 K249X,
2478.9 V247L, V247L,
25410.8
177111.1 I1771T,
177713.4 V1777M, V1777L, V1777L,
41810.2 E418K,
92614.4
2506.1
4096.5 L409V, L409P,
92810.2 L928P,
92514.1 I925F,
165012.7 L1650F,
41711.2
93310.2
2466.1
93512.0 L935P,
17799.6 T1779M,
4124.4 V412D,
92412.7 V924I,
147014.7
92713.6 N927S, N927K, N927K,
2459.2 Q245K,
17769.9
24412.2
176913.9
4156.4 A415T,
164912.6 A1649V,
176813.0 I1768V,
177413.2 N1774D, c.5321_5324dupACTT,
25612.9
40510.5
24810.9
24112.8
42014.5
41913.1 Q419X,
93012.6 c.2787+17_2787+18insACACACACACACACACACACACA, c.2788-6C>T,
25514.1
17729.2 L1772V,
164512.4 T1645M,
23914.4 I239V, I239V ,
25110.2
4104.0 A410V,
178012.8 E1780G
24210.1 A242D,
9299.3
41610.6 Y416C,
4135.9 A413T, A413E,
4085.7
2538.2
4076.5
93610.7
17757.0 F1775V, p.F1775LfsX15,
164210.9 G1642E,
4069.7 N406S, N406K, N406K,
25210.5
4110.0 V411M,
24311.2
9329.2
164713.3
25713.1
93113.8
16469.3
178214.0
View this variant elsewhere
ClinVar → gnomAD → UniProt →