Variant detail

SCN5AG180D

c.539G>A · residue 180 · G → D

Technical Plain language

HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS

NM_000335.5(SCN5A):c.539G>A (G180D)

HGVSc

c.539G>A

cDNA change

c.539G>A

RefSeq transcript

NM_000335.5

Ensembl transcript

ENST00000333535.9

Protein HGVS

G180D

Genomic coordinate

NC_000003.12:g.38662406C>T

ClinVar annotation

Not annotated in local ClinVar field

BrS1 penetrance Moderate risk

48% 90% credible interval 24–73%

0%20%50%100%

Limited evidence · n=0 0 observed BrS1 carriers · 4.85 hypothetical affected and 5.15 hypothetical unaffected

LQT3 penetrance Low risk

4% 90% credible interval 0–21%

0%20%50%100%

Limited evidence · n=0 0 observed LQT3 carriers · 0.2 hypothetical affected and 4.8 hypothetical unaffected

One-sentence summary

Roughly 1 in 2 people who carry G180D are estimated to eventually be diagnosed with Brugada syndrome — moderate penetrance, though evidence is limited (0 carriers). The residue lies in a Hotspot region for BrS1 and a Non_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 48% · LQT3 4%

Model inputHypothetical observationsBrS1 4.85/5.15 · LQT3 0.2/4.8

ObservedObserved carriers (literature + cohorts)0 · Limited evidence

ObservedPopulation observations (gnomAD v4)0 alleles

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

ObservedFunctional / electrophysiologyNA

PredictedStructural contextHotspot

ExternalClinVar classificationNot annotated

ExternalAutomated ACMG reviewNot a classification

ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed

0 BrS1 · 0 LQT3 · 0 unaffected

Model prior: BrS1 4.85 hypothetical affected / 5.15 hypothetical unaffected; LQT3 0.2 hypothetical affected / 4.8 hypothetical unaffected

Limited evidence

Functional data

No published electrophysiology

Predictors and density

REVEL Likely damaging0.978range 0-1

PolyPhen-2 NArange 0-1

BrS1 density Hotspot region0.716range 0-1

LQT3 density Sparse region0.00186range 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	0.2 hypothetical LQT3 affected; 4.85 hypothetical BrS1 affected	4.8 hypothetical LQT3 unaffected; 5.15 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 4.85 hypothetical affected and 5.15 hypothetical unaffected observations; the LQT3 model starts with 0.2 hypothetical affected and 4.8 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 G180D; observed variants link to their detail pages.

Neighbour	Distance (Å)	Observed variants
175	9.2	K175N, K175N,
197	14.8
113	5.9	V113I, V113A,
194	12.4
188	7.4
178	6.3	A178G,
190	13.8	R190G, R190W, R190Q, R190L
128	12.3	c.381dupT,
117	13.7
179	5.9	R179X, R179Q,
119	14.9	P119S, P119L,
177	6.3	L177P,
189	11.6
123	14.0	A123G, A123V,
121	8.1	R121W, R121Q,
198	11.8
124	11.4	A124D,
118	11.6
125	10.9	V125L, V125L,
181	5.3
176	4.8
172	10.8
174	10.0	V174I,
185	6.3	A185T, A185V,
115	9.1	S115G,
186	10.4
182	6.5	C182R, C182Y,
173	9.9
112	8.2	Y112C,
114	4.6
184	4.1	H184R,
191	13.8
116	10.4
187	8.5	T187S, T187S, T187I,
180	0.0	G180V,
170	14.9	F170I,
120	13.2
183	6.9
122	13.3
171	13.8

View this variant elsewhere

ClinVar → gnomAD → UniProt →