Variant detail

KCNQ1R539W

c.1615C>T · residue 539 · Chr11 2797214

Technical Plain language

HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS

NM_000218.3(KCNQ1):c.1615C>T (R539W)

HGVSc

c.1615C>T

cDNA change

c.1615C>T

RefSeq transcript

NM_000218.3

Ensembl transcript

ENST00000155840.12

Protein HGVS

R539W

Genomic coordinate

NC_000011.10:g.2797214C>T

ClinVar annotation

Not annotated in local ClinVar field

LQT1 penetrance High risk

71% 90% credible interval 59-83%

0%20%50%100%

Well-supported · n=28 21 observed LQT1 carriers · 6.07 hypothetical affected and 3.93 hypothetical unaffected

One-sentence summary

Roughly 7 in 10 people who carry R539W are estimated to eventually be diagnosed with Long QT type 1 — high risk penetrance, based on 28 carriers reported so far.

Structure: Hotspot. Functional class: Severe LOF.

Executive summary

Sources used for interpretation

The LQT1 penetrance estimate combines observed carrier counts with a feature-based model starting point. 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 estimate71% · High risk

Model inputHypothetical observations6.07 affected · 3.93 unaffected

ObservedObserved carriers (literature + cohorts)28 · Well-supported

ObservedPopulation observations (gnomAD v4)1 alleles

PredictedIn silico predictorsREVEL · PolyPhen-2 · PROVEAN

ObservedFunctional classSevere LOF

PredictedStructural contextHotspot

ExternalAutomated ACMG reviewNot a classification

ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed

21 LQT1 · 7 unaffected/other · 1 gnomAD

Model prior: 6.07 hypothetical affected · 3.93 hypothetical unaffected

Well-supported

Functional data

Severe LOF

1 published functional study

Predictors and density

REVELLikely damaging0.94range 0-1

LQT1 densityHotspot region0.691range 0-1

PolyPhen-2Probably damaging1range 0-1

PROVEANDeleterious-6.6cutoff <= -2.5

BLAST-PSSM-3lower = less tolerated

Overall4/5

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

PS3review

Published functional studies available

PM1review

Hotspot or high LQT1 density

PM2met · moderate

Absent or extremely rare in population data

PP3met · supporting

Computational predictors support effect

BS1not met

Allele frequency too high for disorder

Reported carrier data

Paper / cohort	Carriers	LQT1 / affected	Unaffected / ambiguous	Other observations	Variant context
PMID 32893267 Year 2020 · clinical carrier record	12	12 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 30758498 Year 2019 · clinical carrier record	3	1 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 29688407 Year 2018 · clinical carrier record	1	0 LQT1	1 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 24681627 Year 2014 · clinical carrier record	0	0 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 24218437 Year 2013 · clinical carrier record	1	1 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 23631430 Year 2013 · clinical carrier record	3	0 LQT1	0 asymptomatic 3 ambiguous	Not separately annotated	Variant R539W Curated carrier-count row
PMID 22949429 Year 2012 · clinical carrier record	6	6 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 19841300 Year 2009 · clinical carrier record	6	6 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 19716085 Year 2009 · clinical carrier record	6	6 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 17192539 Year 2006 · clinical carrier record	1	1 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 15746441 Year 2005 · clinical carrier record	0	0 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 14678125 Year 2003 · clinical carrier record	2	2 LQT1	0 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
PMID 10728423 Year 2000 · clinical carrier record	7	2 LQT1 SCD: 2	5 asymptomatic	Not separately annotated	Variant R539W Curated carrier-count row
gnomAD population observations (v4)	1	0 LQT1	1	Population observations; not known affected cases.	gnomAD v4 allele count.
Combined literature, cohort, and gnomAD	28	21 LQT1	7	Combined totals used in the penetrance estimate.	Curated carrier totals for this variant.
Hypothetical observations from model prior (not observed patients)	10	6.07 hypothetical LQT1 affected	3.93 hypothetical unaffected	Feature-based pseudo-counts added before observed carriers.	Model input; not literature or gnomAD evidence.

Model starting point. The penetrance model starts with 6.07 hypothetical affected and 3.93 hypothetical unaffected observations derived from variant features, then updates that starting point with the real carrier counts above. As observed carrier counts grow, this feature-based starting point has less influence.

Functional studies · researcher detail

PMID	Cell type	HM peak	HM V1/2 act.	HM tau act.	HM tau deact.	HT peak	HT V1/2 act.
10728423	COS	0.17	33.9	1	0.41	0.55	22.5

Nearby variants · researcher detail

Neighbour residue	Distance (A)	Observed variants
538	10.8
362	11.1	K362R, K362del,
537	11.9
531	12.0
541	12.1	V541I,
534	12.2
539	12.7	R539W, R539L, R539Q
536	12.8
361	12.8
532	13.0
540	13.6
366	13.7	R366W, R366Q,
360	13.9	R360ins, R360G, R360M,
542	14.0
527	14.9

External resources

ClinVar Open gnomAD Open UniProt