KCNH2 Variant N633S

Summary of observed carriers, functional annotations, and structural context for KCNH2 N633S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

55%

19/28 effective observations

Total carriers

18

16 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

N633S has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 67% of WT with a standard error of 18%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 3 individuals with LQT2 and 7 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-4.784 0.873 0 0.843 89

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
Japan Cohort 2020 2 0 2
Italy Cohort 2020 2 0 2
France Cohort 2020 8 2 6
24606995 2014 1 0 1
9544837 1998 None 0 2
15840476 2005 1 0 1
19996378 2009 1 0 1
26496715 2015 1 0 1
29650123 2018 1 0
1 0 1
None 0 1
Literature, cohort, and gnomAD – 18 2 16 –
Variant features alone – 10 7 3 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15Å window.

Previously observed variants near N633S.
Neighbour residue Distance (Å) Observed variants
633 0 N633D, N633S, N633I,
632 5 P632A, P632S,
634 5 T634P, T634A, T634S, T634S, T634I,
584 6 G584S, G584R, G584C,
631 6 S631F,
592 6 Q592X,
637 6 E637K, E637G, E637X,
629 6 N629D, N629T, N629S, N629I, N629K, N629K,
638 6 K638E, K638D, K638Del, K638R,
593 7 I593V, I593K, I593T, I593R, I593X,
583 7 I583V,
635 8 N635I,
588 9 N588D, N588K, N588K,
589 9 L589P,
585 9 W585C, W585C,
636 9
616 9 Y616S,
613 9 T613A, T613L, T613K, T613M,
630 9 V630I, V630T, V630A,
630 10 V630I, V630T, V630A,
628 10 G628S, G628R, G628Del, G628D, G628A, G628V,
627 10 F627L, F627fsX, F627X, F627L, F627L,
609 10 D609N, D609G,
594 11
590 11 G590D, G590V,
612 11 V612L, V612L, V612A,
587 11
568 11 W568C, W568C,
641 11 S641P, S641F,
588 11 N588D, N588K, N588K,
628 11 G628S, G628R, G628Del, G628D, G628A, G628V,
591 11 D591N, D591H,
586 11 L586M,
639 11 I639F, I639N,
572 12 G572S, G572R, G572C, G572D,
571 12 I571L, I571V,
595 12 K595E, K595N, K595N,
617 12 F617L, F617V, F617L, F617L,
575 12 E575K,
640 12 F640L, F640V, F640Del, F640L, F640L,
589 13 L589P,
629 13 N629D, N629T, N629S, N629I, N629K, N629K,
631 13 S631F,
614 13 A614T, A614V,
606 13 S606Del, S606P, S606F,
605 13 P605L,
642 13 I642V, I642Del
585 13 W585C, W585C,
617 13 F617L, F617V, F617L, F617L,
591 13 D591N, D591H,
610 13
577 14
592 14 Q592X,
608 14
626 14 G626S, G626A, G626V,
586 14 L586M,
576 14
615 14 L615V, L615F,
620 14 S620G, S620I,
590 14 G590D, G590V,
626 15 G626S, G626A, G626V,
613 15 T613A, T613L, T613K, T613M,
621 15 S621R, S621N, S621R, S621R,
614 15 A614T, A614V,