KCNH2 Variant W585C

Summary of observed carriers, functional annotations, and structural context for KCNH2 W585C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

41%

4/11 effective observations

Total carriers

1

1 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

W585C has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 8%. 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 (%)
-12.303 1.0 -3 0.979 87

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
10973849 2000 1 0 1
Literature, cohort, and gnomAD – 1 0 1 –
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 W585C.
Neighbour residue Distance (Å) Observed variants
585 0 W585C, W585C,
586 4 L586M,
568 5 W568C, W568C,
584 6 G584S, G584R, G584C,
572 6 G572S, G572R, G572C, G572D,
589 7 L589P,
637 7 E637K, E637G, E637X,
588 7 N588D, N588K, N588K,
630 7 V630I, V630T, V630A,
631 7 S631F,
613 7 T613A, T613L, T613K, T613M,
614 8 A614T, A614V,
569 8 Y569H, Y569C, Y569X,
571 8 I571L, I571V,
587 8
632 8 P632A, P632S,
610 8
617 8 F617L, F617V, F617L, F617L,
633 9 N633D, N633S, N633I,
573 9
634 9 T634P, T634A, T634S, T634S, T634I,
570 9
583 10 I583V,
590 10 G590D, G590V,
565 10
592 10 Q592X,
636 10
609 11 D609N, D609G,
576 11
629 11 N629D, N629T, N629S, N629I, N629K, N629K,
605 11 P605L,
640 11 F640L, F640V, F640Del, F640L, F640L,
575 11 E575K,
616 11 Y616S,
612 11 V612L, V612L, V612A,
591 11 D591N, D591H,
567 11 I567T, I567M,
628 12 G628S, G628R, G628Del, G628D, G628A, G628V,
618 12 T618S, T618S,
638 12 K638E, K638D, K638Del, K638R,
566 12 C566S, C566R, C566G, C566S, C566F,
593 12 I593V, I593K, I593T, I593R, I593X,
597 12 Y597H, Y597C,
615 12 L615V, L615F,
611 12 Y611D,
641 12 S641P, S641F,
629 12 N629D, N629T, N629S, N629I, N629K, N629K,
574 13 M574L, M574V, M574L,
431 13 F431L, F431L, F431L,
606 13 S606Del, S606P, S606F,
564 13 L564L,
638 13 K638E, K638D, K638Del, K638R,
627 13 F627L, F627fsX, F627X, F627L, F627L,
607 13
635 13 N635I,
604 13 G604S, G604C, G604D,
633 13 N633D, N633S, N633I,
577 13
620 14 S620G, S620I,
595 14 K595E, K595N, K595N,
621 14 S621R, S621N, S621R, S621R,
592 14 Q592X,
430 14
639 14 I639F, I639N,
596 14 P596T, P596S, P596R, P596L,
632 14 P632A, P632S,
616 14 Y616S,
627 14 F627L, F627fsX, F627X, F627L, F627L,
628 15 G628S, G628R, G628Del, G628D, G628A, G628V,
635 15 N635I,
644 15 V644I, V644F
593 15 I593V, I593K, I593T, I593R, I593X,
626 15 G626S, G626A, G626V,
594 15