Variant detail

KCNQ1K422R

c.1265A>G · residue 422 · Chr11 2609956
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000218.3(KCNQ1):c.1265A>G (K422R)
HGVSc
c.1265A>G
cDNA change
c.1265A>G
RefSeq transcript
NM_000218.3
Ensembl transcript
ENST00000155840.12
Protein HGVS
K422R
Genomic coordinate
NC_000011.10:g.2609956A>G
ClinVar annotation
Not annotated in local ClinVar field
LQT1 penetrance Low risk
15% 90% credible interval 2-36%
0%20%50%100%

Limited evidence · n=1 0 observed LQT1 carriers · 1.69 hypothetical affected and 8.31 hypothetical unaffected

One-sentence summary

Roughly 1 in 7 people who carry K422R are estimated to eventually be diagnosed with Long QT type 1 — low risk penetrance, based on 1 carriers reported so far.

Structure: Mild_Hotspot. Functional class: NA.

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 estimate15% · Low risk
Model inputHypothetical observations1.69 affected · 8.31 unaffected
ObservedObserved carriers (literature + cohorts)1 · Limited evidence
ObservedPopulation observations (gnomAD v4)1 alleles
PredictedIn silico predictorsREVEL · PolyPhen-2 · PROVEAN
ObservedFunctional classNA
PredictedStructural contextMild_Hotspot
ExternalAutomated ACMG reviewNot a classification
ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed
1
0 LQT1 · 1 unaffected/other · 1 gnomAD
Model prior: 1.69 hypothetical affected · 8.31 hypothetical unaffected
Limited evidence
Functional data
NA
0 published functional studies
Predictors and density
REVELUncertain0.628range 0-1
LQT1 densitySparse region0.171range 0-1
PolyPhen-2Possibly damaging0.94range 0-1
PROVEANNeutral-0.9cutoff <= -2.5
BLAST-PSSM2lower = less tolerated
Overall3/5
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
PS3not met
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
gnomAD population observations (v4) 1 0 LQT1 1 Population observations; not known affected cases. gnomAD v4 allele count.
Combined literature, cohort, and gnomAD 1 0 LQT1 1 Combined totals used in the penetrance estimate. Curated carrier totals for this variant.
Hypothetical observations from model prior (not observed patients) 10 1.69 hypothetical LQT1 affected 8.31 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 1.69 hypothetical affected and 8.31 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.

Nearby variants · researcher detail
Neighbour residueDistance (A)Observed variants
4220.0K422T, K422R,
4213.8K421N, K421N,
4233.8
4205.4K420E, K420N, K420N,
4245.4K424T,
4196.6
4256.6L425V,
4187.6V418I,
4267.6
4178.5V417M,
4278.5
4169.3V416M,
4289.3D428G,
41510.1
42910.1N429S,
41410.7
43010.7
41311.4K413R,
43111.4V431L, V431L,
41212.0P412S,
43212.0T432I, T432A
41112.6
43312.6P433A,
41013.2
43413.2G434R, G434R,
40913.7
43513.7
40814.2P408A,
43614.2
40714.7
43714.7M437V,
External resources
ClinVar Open gnomAD Open UniProt