Variant detail

SCN5AR1623X

c.4867X · residue 1623 · R → X
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000335.5(SCN5A):c.4867X (R1623X)
HGVSc
c.4867X
cDNA change
c.4867X
RefSeq transcript
NM_000335.5
Ensembl transcript
ENST00000333535.9
Protein HGVS
R1623X
Genomic coordinate
Not available in current dataset
ClinVar annotation
Not annotated in local ClinVar field
BrS1 penetrance Moderate risk
38% 90% credible interval 22–56%
0%20%50%100%

Emerging evidence · n=11 5 observed BrS1 carriers · 2.96 hypothetical affected and 7.04 hypothetical unaffected

LQT3 penetrance Low risk
10% 90% credible interval 1–23%
0%20%50%100%

Emerging evidence · n=11 0 observed LQT3 carriers · 1.52 hypothetical affected and 3.48 hypothetical unaffected

One-sentence summary

Roughly 1 in 3 people who carry R1623X are estimated to eventually be diagnosed with Brugada syndrome — moderate penetrance, though evidence is limited (11 carriers). The residue lies in a Mild_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 38% · LQT3 10%
Model inputHypothetical observationsBrS1 2.96/7.04 · LQT3 1.52/3.48
ObservedObserved carriers (literature + cohorts)11 · Emerging evidence
ObservedPopulation observations (gnomAD v4)0 alleles
PredictedIn silico predictorsREVEL · PolyPhen-2 · PROVEAN · BLAST-PSSM
ObservedFunctional / electrophysiologyLOF
PredictedStructural contextMild_Hotspot
ExternalClinVar classificationNot annotated
ExternalAutomated ACMG reviewNot a classification
ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed
11
5 BrS1 · 0 LQT3 · 6 unaffected
Model prior: BrS1 2.96 hypothetical affected / 7.04 hypothetical unaffected; LQT3 1.52 hypothetical affected / 3.48 hypothetical unaffected
Emerging evidence
Functional data
LOF
13 published electrophysiology studies
Predictors and density
REVEL —range 0-1
PolyPhen-2 NArange 0-1
BrS1 density Sparse region0.287range 0-1
LQT3 density Sparse region0.391range 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
PS3met · strong
Functional studies show damaging effect
PM1review
Hotspot or high BrS1/LQT3 density
PM2met · moderate
Absent / extremely rare in population databases
PP3not met
Multiple computational predictors support deleterious
BS1not met
Allele frequency too high for disorder
BP4met · supporting
Computational predictors suggest no impact

Reported carrier data

Paper / cohort Carriers LQT3 / BrS1 Unaffected Other observations Variant context
Year 2017 · clinical carrier record
1 0 LQT3 0 1 other phenotype
ARVD
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2005 · clinical carrier record
1 0 LQT3
1 BrS1 		0 Not separately annotated
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2003 · clinical carrier record
4 0 LQT3 3 1 other phenotype
SSS
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2005 · clinical carrier record
5 0 LQT3
2 BrS1 		3 Not separately annotated
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2012 · clinical carrier record
1 0 LQT3
1 BrS1 		0 Not separately annotated
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2017 · clinical carrier record
1 0 LQT3
1 BrS1 		0 Not separately annotated
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2010 · clinical carrier record
1 0 LQT3
1 BrS1 		0 Not separately annotated
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2010 · clinical carrier record
1 0 LQT3
1 BrS1 		0 Not separately annotated
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2018 · clinical carrier record
1 0 LQT3
1 BrS1 		0 Not separately annotated
Variant R1623X
Residue 1623
Curated carrier-count row
Year 2018 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant R1623X
Residue 1623
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		 1.52 hypothetical LQT3 affected;
2.96 hypothetical BrS1 affected		 3.48 hypothetical LQT3 unaffected;
7.04 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 11 0 LQT3
5 BrS1		 6 Combined totals used in the dual penetrance estimates. Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 2.96 hypothetical affected and 7.04 hypothetical unaffected observations; the LQT3 model starts with 1.52 hypothetical affected and 3.48 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)
28069705 2017 0———
28552050 2017 0———
16325048 2005HEK 0———
20384651 2010 0———
14523039 2003HEK-tSA201 0———
20539757 2010 ————
15840483 2005 ————
22885917 2012 ————
28341781 2017 ————
20129283 2010 ————
20129283 2010 ————
29574140 2018 ————
30059973 2018 ————
View this variant elsewhere
ClinVar → gnomAD → UniProt →