Variant detail

KCNH2S621R

c.1863C>G · residue 621 · S → R
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000238.4(KCNH2):c.1863C>G (p.Ser621Arg)
HGVSc
c.1863C>G
cDNA change
c.1863C>G
RefSeq transcript
NM_000238.4
Ensembl transcript
ENST00000262186.10
Protein HGVS
p.Ser621Arg
Genomic coordinate
NC_000007.14:g.150648618G>C
ClinVar annotation
Not annotated in local ClinVar field
LQT2 penetrance Moderate risk
36% 90% credible interval 15-59%
0%20%50%100%

Limited evidence · n=2 1 observed LQT2 carriers · 3.29 hypothetical affected and 6.71 hypothetical unaffected

One-sentence summary

Roughly 1 in 3 people who carry S621R are estimated to eventually be diagnosed with Long QT type 2 — moderate risk penetrance, based on 2 carriers reported so far.

Structure: Hotspot. Functional evidence: MAVE 30% WT.

Executive summary

Sources used for interpretation

The LQT2 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 estimate36% · Moderate risk
Model inputHypothetical observations3.29 affected · 6.71 unaffected
ObservedObserved carriers (literature + cohorts)2 · Limited evidence
ObservedPopulation observations (gnomAD v4)0 alleles
PredictedIn silico predictorsREVEL · PolyPhen-2 · PROVEAN · BLAST-PSSM
ObservedFunctional / MAVE dataModerate trafficking loss · 0 studies
PredictedStructural contextHotspot
ExternalAutomated ACMG reviewNot a classification
ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed
2
1 LQT2 · 1 unaffected · 0 gnomAD
Model prior: 3.29 hypothetical affected · 6.71 hypothetical unaffected
Limited evidence
Functional data
Moderate trafficking loss
MAVE 30% WT · 0 published functional studies
Predictors and density
REVELLikely damaging0.974range 0-1
LQT2 densityHotspot region0.748range 0-1
PolyPhen-2Probably damaging0.999range 0-1
PROVEANDeleterious-4.88cutoff <= -2.5
BLAST-PSSM-1lower = 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
PS3met · strong/moderate
Functional studies or MAVE support effect
PM1review
Hotspot or high LQT2 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 LQT2 / affected Unaffected / ambiguous Other observations Variant context
Year 2010 · clinical carrier record
2 1 LQT2
SCD: 1 		1 unaffected / ambiguous
1 ambiguous 		Not separately annotated
Variant S621R
Curated carrier-count row
gnomAD population observations (v4) 0 0 LQT2 0 Population observations; not known affected cases. gnomAD v4 allele count.
Combined literature, cohort, and gnomAD 2 1 LQT2 1 Combined totals used in the penetrance estimate. Curated carrier totals for this variant.
Hypothetical observations from model prior (not observed patients) 10 3.29 hypothetical LQT2 affected 6.71 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 3.29 hypothetical affected and 6.71 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
6210.0 S621R, S621N, S621R, S621R,
6204.0 S620G, S620I,
6224.5 L622F,
6185.4 T618S, T618S,
6445.5 V644I, V644F,
6175.6 F617L, F617V, F617L, F617L,
6456.0 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
6236.1 T623I,
6246.2 S624R, S624N, S624R, S624R,
6256.4 V625E,
6416.6 S641P, S641F,
6266.9 G626S, G626A, G626V,
6256.9 V625E,
6277.2 F627L, F627fsX, F627X, F627L, F627L,
6197.4
6487.7 G648A,
6268.7 G626S, G626A, G626V,
6408.8 F640L, F640V, F640Del, F640L, F640L,
6238.9 T623I,
6209.2 S620G, S620I,
5649.3 L564L,
6169.3 Y616S,
6249.4 S624R, S624N, S624R, S624R,
6279.4 F627L, F627fsX, F627X, F627L, F627L,
6459.5 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
6429.6 I642V, I642Del,
6479.6
5619.6 A561T, A561P, A561V,
6439.7
6499.8
6309.9 V630I, V630T, V630A,
56810.2 W568C, W568C,
63210.3 P632A, P632S,
61510.3 L615V, L615F,
65210.4 Y652X,
64610.5
62410.5 S624R, S624N, S624R, S624R,
63110.5 S631F,
61610.5 Y616S,
61410.5 A614T, A614V,
56511.1
62811.1 G628S, G628R, G628Del, G628D, G628A, G628V,
61911.2
55711.2
62611.4 G626S, G626A, G626V,
56011.4 I560fsX, I560M,
64211.7 I642V, I642Del,
65111.7 M651K,
62511.9 V625E,
63812.1 K638E, K638D, K638Del, K638R,
62512.2 V625E,
63712.3 E637K, E637G, E637X,
64112.4 S641P, S641F,
61312.4 T613A, T613L, T613K, T613M,
62112.5 S621R, S621N, S621R, S621R,
62112.5 S621R, S621N, S621R, S621R,
62812.6 G628S, G628R, G628Del, G628D, G628A, G628V,
62612.6 G626S, G626A, G626V,
62412.6 S624R, S624N, S624R, S624R,
64912.7
62912.8 N629D, N629T, N629S, N629I, N629K, N629K,
62912.9 N629D, N629T, N629S, N629I, N629K, N629K,
63912.9 I639F, I639N,
65013.0 L650X,
62213.0 L622F,
56713.1 I567T, I567M,
64613.1
55813.2 A558P, A558E, A558V,
65213.4 Y652X,
58513.6 W585C, W585C,
61714.0 F617L, F617V, F617L, F617L,
63814.0 K638E, K638D, K638Del, K638R,
62714.1 F627L, F627fsX, F627X, F627L, F627L,
65314.2
64814.2 G648A,
56214.2 H562P, H562R, H562Q, H562Q,
64414.2 V644I, V644F,
61814.3 T618S, T618S,
62014.4 S620G, S620I,
63214.4 P632A, P632S,
65614.4 F656L, F656L, F656L
61214.4 V612L, V612L, V612A,
56614.5 C566S, C566R, C566G, C566S, C566F,
62314.5 T623I,
63014.6 V630I, V630T, V630A,
61514.6 L615V, L615F,
63614.8
63314.8 N633D, N633S, N633I,
56314.9 W563G, W563C, W563C, W563X,
57114.9 I571L, I571V,
External resources
ClinVar Open gnomAD Open UniProt