KCNH2 Variant T618S

Summary of observed carriers, functional annotations, and structural context for KCNH2 T618S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

29%

90% CI: 18.8% – 57.4%

5/16 effective observations

Total carriers

6

3 LQT2 · 3 unaffected

Functional studies

0

Publications with functional data

T618S has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 129% of WT with a standard error of 10%. 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-3.794 0.873 1 0.909 68

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 6 3 3
Literature, cohort, and gnomAD – 6 3 3 –
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 T618S.
Neighbour residue Distance (Å) Observed variants
618 0 T618S, T618S,
617 4 F617L, F617V, F617L, F617L,
619 5
561 5 A561T, A561P, A561V,
564 5 L564L,
621 5 S621R, S621N, S621R, S621R,
615 5 L615V, L615F,
622 6 L622F,
620 6 S620G, S620I,
565 6
614 6 A614T, A614V,
644 7 V644I, V644F,
568 8 W568C, W568C,
616 8 Y616S,
640 8 F640L, F640V, F640Del, F640L, F640L,
623 8 T623I,
560 8 I560fsX, I560M,
641 9 S641P, S641F,
562 9 H562P, H562R, H562Q, H562Q,
613 9 T613A, T613L, T613K, T613M,
642 9 I642V, I642Del,
567 9 I567T, I567M,
558 9 A558P, A558E, A558V,
557 9
566 9 C566S, C566R, C566G, C566S, C566F,
645 9 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
630 10 V630I, V630T, V630A,
648 10 G648A,
611 10 Y611D,
645 10 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
612 10 V612L, V612L, V612A,
625 10 V625E,
647 10
626 11 G626S, G626A, G626V,
563 11 W563G, W563C, W563C, W563X,
643 11
624 11 S624R, S624N, S624R, S624R,
627 11 F627L, F627fsX, F627X, F627L, F627L,
627 11 F627L, F627fsX, F627X, F627L, F627L,
559 11 L559F, L559H,
641 12 S641P, S641F,
585 12 W585C, W585C,
625 12 V625E,
631 12 S631F,
638 12 K638E, K638D, K638Del, K638R,
646 12
632 12 P632A, P632S,
651 12 M651K,
637 12 E637K, E637G, E637X,
642 12 I642V, I642Del,
569 12 Y569H, Y569C, Y569X,
571 13 I571L, I571V,
652 13 Y652X
628 13 G628S, G628R, G628Del, G628D, G628A, G628V,
649 13
570 13
629 13 N629D, N629T, N629S, N629I, N629K, N629K,
639 13 I639F, I639N,
646 13
556 13
626 14 G626S, G626A, G626V,
649 14
632 14 P632A, P632S,
610 14
623 14 T623I,
643 14
609 14 D609N, D609G,
639 14 I639F, I639N,
644 14 V644I, V644F,
638 14 K638E, K638D, K638Del, K638R,
624 14 S624R, S624N, S624R, S624R,
616 14 Y616S,
621 14 S621R, S621N, S621R, S621R,
620 14 S620G, S620I,
426 14 P426H,
624 15 S624R, S624N, S624R, S624R,
636 15
431 15 F431L, F431L, F431L,
423 15
554 15
572 15 G572S, G572R, G572C, G572D,
650 15 L650X,
626 15 G626S, G626A, G626V,