Variant detail

KCNQ1G269S

c.805G>A · residue 269 · Chr11 2594100
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000218.3(KCNQ1):c.805G>A (G269S)
HGVSc
c.805G>A
cDNA change
c.805G>A
RefSeq transcript
NM_000218.3
Ensembl transcript
ENST00000155840.12
Protein HGVS
G269S
Genomic coordinate
NC_000011.10:g.2594100G>A
ClinVar annotation
Not annotated in local ClinVar field
LQT1 penetrance High risk
61% 90% credible interval 50-71%
0%20%50%100%

Well-supported · n=48 28 observed LQT1 carriers · 7.16 hypothetical affected and 2.84 hypothetical unaffected

One-sentence summary

Roughly 6 in 10 people who carry G269S are estimated to eventually be diagnosed with Long QT type 1 — high risk penetrance, based on 48 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 estimate61% · High risk
Model inputHypothetical observations7.16 affected · 2.84 unaffected
ObservedObserved carriers (literature + cohorts)48 · 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
48
28 LQT1 · 20 unaffected/other · 1 gnomAD
Model prior: 7.16 hypothetical affected · 2.84 hypothetical unaffected
Well-supported
Functional data
Severe LOF
1 published functional study
Predictors and density
REVELLikely damaging0.934range 0-1
LQT1 densityHotspot region0.729range 0-1
PolyPhen-2Probably damaging0.998range 0-1
PROVEANDeleterious-5.83cutoff <= -2.5
BLAST-PSSM0lower = 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
Year 2020 · clinical carrier record
17 17 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2020 · clinical carrier record
0 0 LQT1
2 JLNS 		0 asymptomatic
2 homozygous 		Not separately annotated
Variant G269S
Curated carrier-count row
Year 2019 · clinical carrier record
20 6 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2018 · clinical carrier record
19 6 LQT1
SCD: 4 		12 asymptomatic
1 ambiguous 		Not separately annotated
Variant G269S
Curated carrier-count row
Year 2018 · clinical carrier record
1 1 LQT1 0 asymptomatic TdP
Variant G269S
Curated carrier-count row
Year 2016 · clinical carrier record
1 1 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2014 · clinical carrier record
0 0 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2013 · clinical carrier record
3 0 LQT1 0 asymptomatic
3 ambiguous 		Not separately annotated
Variant G269S
Curated carrier-count row
Year 2012 · clinical carrier record
43 1 LQT1 0 asymptomatic
42 ambiguous 		Not separately annotated
Variant G269S
Curated carrier-count row
Year 2012 · clinical carrier record
1 0 LQT1 0 asymptomatic
1 ambiguous 		SUDS
Variant G269S
Curated carrier-count row
Year 2009 · clinical carrier record
10 10 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2009 · clinical carrier record
41 41 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2008 · clinical carrier record
20 3 LQT1 0 asymptomatic
17 unknown 		RWS
Variant G269S
Curated carrier-count row
Year 2008 · clinical carrier record
25 0 LQT1 0 asymptomatic
25 ambiguous 		Not separately annotated
Variant G269S
Curated carrier-count row
Year 2007 · clinical carrier record
25 25 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2007 · clinical carrier record
1 0 LQT1
SCD: 1 		0 asymptomatic
1 ambiguous 		Not separately annotated
Variant G269S
Curated carrier-count row
Year 2003 · clinical carrier record
2 2 LQT1 0 asymptomatic Not separately annotated
Variant G269S
Curated carrier-count row
Year 2002 · clinical carrier record
8 1 LQT1
1 JLNS 		7 asymptomatic
2 homozygous 		Not separately annotated
Variant G269S
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 48 28 LQT1 20 Combined totals used in the penetrance estimate. Curated carrier totals for this variant.
Hypothetical observations from model prior (not observed patients) 10 7.16 hypothetical LQT1 affected 2.84 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 7.16 hypothetical affected and 2.84 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
PMIDCell typeHM peakHM V1/2 act.HM tau act.HM tau deact.HT peakHT V1/2 act.
24184248CHO0.1570.710.40.327.8
Nearby variants · researcher detail
Neighbour residueDistance (A)Observed variants
2690.0G269D, G269S, G269del,
2684.4I268V, I268S,
2724.8G272D, G272S, G272V,
2715.2
2736.2L273F, L273V, L273R,
2676.8Y267C
2748.1I274V,
2649.1
2759.6F275del,
27610.0S276del,
30610.8G306V, G306R, G306R,
24810.8W248C, W248C, W248R, W248R,
24710.9T247I,
23810.9M238V, M238L, M238L,
33411.2V334A,
27711.5S277L, S277del, S277P, S277W,
23911.7
33612.0A336S,
33512.1F335L, F335L, F335L,
33912.5F339del, F339S,
30312.6L303P,
23512.6I235N,
33312.8
24213.0D242N, D242Y,
25013.3L250H, L250P,
26113.6E261K, E261D, E261D, E261G, E261Q,
25113.9L251P, L251Q,
26614.0L266P,
33014.1
27914.2F279I,
24114.2V241F, V241I, V241G,
33114.3
35114.3F351L, F351L, F351L, F351S,
27814.3Y278H,
33214.5
24614.5
23614.5L236Q, L236R,
34714.7L347P, L347R,
27014.8F270S,
24514.9G245V,
External resources
ClinVar Open gnomAD Open UniProt