KCNH2 Variant S606F

Summary of observed carriers, functional annotations, and structural context for KCNH2 S606F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

40%

5/13 effective observations

Total carriers

3

2 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

S606F 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 0%. 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 (%)
-5.461 0.992 -3 0.889 81

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
France Cohort 2020 2 1 1
22104571 2011 1 0 1 epilepsy
Literature, cohort, and gnomAD – 3 1 2 –
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 S606F.
Neighbour residue Distance (Å) Observed variants
606 0 S606Del, S606P, S606F,
605 4 P605L,
607 4
609 5 D609N, D609G,
610 5
608 6
604 7 G604S, G604C, G604D,
595 7 K595E, K595N, K595N,
635 9 N635I,
593 9 I593V, I593K, I593T, I593R, I593X,
612 9 V612L, V612L, V612A,
589 9 L589P,
603 10 G603D,
613 10 T613A, T613L, T613K, T613M,
594 10
611 10 Y611D,
431 10 F431L, F431L, F431L,
586 11 L586M,
590 11 G590D, G590V,
569 11 Y569H, Y569C, Y569X,
597 11 Y597H, Y597C,
634 12 T634P, T634A, T634S, T634S, T634I,
596 12 P596T, P596S, P596R, P596L,
614 12 A614T, A614V,
638 12 K638E, K638D, K638Del, K638R,
427 12 Y427H, Y427S, Y427C,
585 13 W585C, W585C,
592 13 Q592X,
633 13 N633D, N633S, N633I,
432 13
636 13
573 14
587 14
591 14 D591N, D591H,
639 14 I639F, I639N
430 14
615 14 L615V, L615F,
588 14 N588D, N588K, N588K,
572 15 G572S, G572R, G572C, G572D,
583 15 I583V,
565 15
616 15 Y616S,
566 15 C566S, C566R, C566G, C566S, C566F,