KCNH2 Variant F557S

Summary of observed carriers, functional annotations, and structural context for KCNH2 F557S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

26%

2/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F557S 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 12%. 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 (%)
-7.668 1.0 -3 0.945 66

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
Literature, cohort, and gnomAD – 0 0 0 –
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 F557S.
Neighbour residue Distance (Å) Observed variants
557 0
558 5 A558P, A558E, A558V,
560 6 I560fsX, I560M,
554 6
556 6
619 7
561 7 A561T, A561P, A561V,
622 7 L622F,
651 7 M651K,
646 7
655 7
555 7
656 8 F656L, F656L, F656L,
559 8 L559F, L559H,
553 8 L553V,
649 8
652 8 Y652X,
623 8 T623I,
648 9 G648A,
618 9 T618S, T618S,
645 10 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
650 10 L650X,
562 10 H562P, H562R, H562Q, H562Q,
564 11 L564L,
642 11 I642V, I642Del,
552 11 L552S,
615 11 L615V, L615F,
647 11
563 11 W563G, W563C, W563C, W563X,
654 11
659 11
648 11 G648A,
653 11
621 11 S621R, S621N, S621R, S621R,
550 11
620 11 S620G, S620I,
551 11 F551L, F551L, F551L,
647 12
644 12 V644I, V644F,
650 12 L650X,
649 12
643 12
624 12 S624R, S624N, S624R, S624R,
658 12
657 13 G657S, G657V,
565 13
653 13
644 13 V644I, V644F,
617 14 F617L, F617V, F617L, F617L,
419 14
423 14
422 14 A422T,
625 14 V625E,
549 14 V549M,
641 14 S641P, S641F,
616 14 Y616S,
660 14 S660L
614 14 A614T, A614V,
651 14 M651K,
645 15 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
566 15 C566S, C566R, C566G, C566S, C566F,
624 15 S624R, S624N, S624R, S624R,
652 15 Y652X,
611 15 Y611D,
646 15