Variant detail

SCN5AR1632H

c.4895G>A · residue 1632 · R → H
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000335.5(SCN5A):c.4895G>A (R1632H)
HGVSc
c.4895G>A
cDNA change
c.4895G>A
RefSeq transcript
NM_000335.5
Ensembl transcript
ENST00000333535.9
Protein HGVS
R1632H
Genomic coordinate
NC_000003.12:g.38592968C>T
ClinVar annotation
Not annotated in local ClinVar field
BrS1 penetrance High risk
55% 90% credible interval 38–71%
0%20%50%100%

Emerging evidence · n=15 10 observed BrS1 carriers · 3.69 hypothetical affected and 6.31 hypothetical unaffected

LQT3 penetrance Low risk
4% 90% credible interval 0–12%
0%20%50%100%

Emerging evidence · n=15 0 observed LQT3 carriers · 0.726 hypothetical affected and 4.27 hypothetical unaffected

One-sentence summary

Roughly 1 in 2 people who carry R1632H are estimated to eventually be diagnosed with Brugada syndrome — high penetrance, though evidence is limited (15 carriers). The residue lies in a 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 55% · LQT3 4%
Model inputHypothetical observationsBrS1 3.69/6.31 · LQT3 0.726/4.27
ObservedObserved carriers (literature + cohorts)15 · Emerging evidence
ObservedPopulation observations (gnomAD v4)2 alleles
PredictedIn silico predictorsREVEL · PolyPhen-2 · PROVEAN · BLAST-PSSM
ObservedFunctional / electrophysiologyNormal
PredictedStructural contextHotspot
ExternalClinVar classificationNot annotated
ExternalAutomated ACMG reviewNot a classification
ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed
15
10 BrS1 · 0 LQT3 · 5 unaffected
Model prior: BrS1 3.69 hypothetical affected / 6.31 hypothetical unaffected; LQT3 0.726 hypothetical affected / 4.27 hypothetical unaffected
Emerging evidence
Functional data
Normal
7 published electrophysiology studies
Predictors and density
REVEL Likely damaging0.98range 0-1
PolyPhen-2 Probably damaging0.998range 0-1
BrS1 density Hotspot region0.621range 0-1
LQT3 density Sparse region0.149range 0-1
PROVEAN Deleterious-4.63cutoff <= -2.5
BLAST-PSSM 0.45lower = 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
Year 2003 · clinical carrier record
2 0 LQT3 1 1 other phenotype
SSS
Variant R1632H
Residue 1632
Curated carrier-count row
Year 2014 · clinical carrier record
5 0 LQT3
1 BrS1 		1 3 other phenotype
SSS
Variant R1632H
Residue 1632
Curated carrier-count row
Year 2017 · clinical carrier record
10 0 LQT3
9 BrS1 		1 Not separately annotated
Variant R1632H
Residue 1632
Curated carrier-count row
Year 2018 · clinical carrier record
8 0 LQT3
2 BrS1 		6 Not separately annotated
Variant R1632H
Residue 1632
Curated carrier-count row
gnomAD population observations (v4) 2 0 LQT3
0 BrS1		 2 Population observations; not known affected cases. gnomAD v4 allele count.
Hypothetical observations from model prior (not observed patients) 5 LQT3 prior;
10 BrS1 prior		 0.726 hypothetical LQT3 affected;
3.69 hypothetical BrS1 affected		 4.27 hypothetical LQT3 unaffected;
6.31 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 15 0 LQT3
10 BrS1		 5 Combined totals used in the dual penetrance estimates. Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 3.69 hypothetical affected and 6.31 hypothetical unaffected observations; the LQT3 model starts with 0.726 hypothetical affected and 4.27 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)
14523039 2003HEK-tSA201 1001.3-14.6—
20384651 2010HEK 1-2.4-22—
24948852 2014 ————
28781330 2017 ————
20539757 2010 ————
29709101 2018 ————
32533946 2020HEK 65-10.9-12—
Structural neighbours · researcher detail

Residues within 15 Å of R1632H; observed variants link to their detail pages.

NeighbourDistance (Å)Observed variants
152513.3 V1525M, V1525A,
162710.7
158612.1
156714.4 F1567L, F1567L, F1567L,
162414.0 V1624I,
153611.9
15387.1
15318.9
16356.1
158714.8 F1587V,
16348.2 L1634P,
15348.4
154211.2
157512.3 C1575S, C1575S,
26014.5
157110.8 F1571C,
157014.3 p.1570_F1571insI, I1570V, p.I1570dup,
152914.0
159913.6
16305.8 I1630V, I1630R,
153210.6 V1532I, V1532F,
162612.0 R1626C, R1626H, R1626P, R1626L,
164414.6 R1644C, R1644H, R1644L
162511.9
26215.0 S262G,
159613.4 F1596I, F1596C,
16287.8
15899.4
16320.0 R1632C, R1632H, R1632L,
159713.1 V1597M,
153011.5
15399.4 C1539Y, C1539F,
157314.7
15355.3
153710.7
15948.8 F1594S,
163813.7 R1638X, R1638Q,
25911.9
158814.2 T1588I,
16336.4
15915.2 W1591X,
159311.1 I1593M,
15957.1
163711.9
16368.3
26312.8 V263I,
16295.3 R1629G, R1629X, R1629Q,
157410.0 c.4719C>T, E1574K,
153311.8 T1533I,
154111.7
15928.0
157810.9 c.4732_4733dupAA,
154013.1
152814.5
16314.9 G1631D,
15909.3
164714.9
159811.6 V1598A,
157715.0
View this variant elsewhere
ClinVar → gnomAD → UniProt →