KCNH2 Variant I639N

Summary of observed carriers, functional annotations, and structural context for KCNH2 I639N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

24%

3/12 effective observations

Total carriers

2

1 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

I639N has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

Variant features alone are equivalent to phenotyping 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-6.398 0.997 -4 0.969 82

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 1 1
Literature, cohort, and gnomAD – 2 1 1 –
Variant features alone – 10 8 2 –

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 I639N.
Neighbour residue Distance (Å) Observed variants
639 0 I639F, I639N,
636 5
642 5 I642V, I642Del,
638 6 K638E, K638D, K638Del, K638R,
640 6 F640L, F640V, F640Del, F640L, F640L,
641 6 S641P, S641F,
635 7 N635I,
612 7 V612L, V612L, V612A,
643 7
637 7 E637K, E637G, E637X,
616 8 Y616S,
634 9 T634P, T634A, T634S, T634S, T634I,
615 9 L615V, L615F,
632 9 P632A, P632S,
644 9 V644I, V644F,
608 10
613 10 T613A, T613L, T613K, T613M,
571 10 I571L, I571V,
645 10 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
611 10 Y611D,
609 10 D609N, D609G,
619 11
568 11 W568C, W568C,
646 11
614 11 A614T, A614V,
633 11 N633D, N633S, N633I,
567 12 I567T, I567M,
575 12 E575K,
647 13
564 13 L564L,
627 13 F627L, F627fsX, F627X, F627L, F627L,
621 13 S621R, S621N, S621R, S621R,
620 13 S620G, S620I,
631 13 S631F,
617 13 F617L, F617V, F617L, F617L,
618 13 T618S, T618S,
570 13
558 13 A558P, A558E, A558V,
572 14 G572S, G572R, G572C, G572D,
617 14 F617L, F617V, F617L, F617L,
562 14 H562P, H562R, H562Q, H562Q,
629 14 N629D, N629T, N629S, N629I, N629K, N629K,
561 14 A561T, A561P, A561V,
585 14 W585C, W585C,
610 14
565 14
618 14 T618S, T618S,
606 14 S606Del, S606P, S606F,
584 14 G584S, G584R, G584C,
607 14
630 15 V630I, V630T, V630A,
648 15 G648A
623 15 T623I,
593 15 I593V, I593K, I593T, I593R, I593X,