KCNH2 Variant S641F

Summary of observed carriers, functional annotations, and structural context for KCNH2 S641F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

40%

90% CI: 28.7% – 70.0%

7/15 effective observations

Total carriers

5

4 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

S641F has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

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 (%)
-5.701 0.997 -3 0.945 85

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 3 1 2
Italy Cohort 2020 1 0 1
15840476 2005 1 0 1
Literature, cohort, and gnomAD – 5 1 4 –
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 S641F.
Neighbour residue Distance (Å) Observed variants
641 0 S641P, S641F,
642 4 I642V, I642Del,
640 5 F640L, F640V, F640Del, F640L, F640L,
645 5 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
644 5 V644I, V644F,
616 6 Y616S,
643 6
638 6 K638E, K638D, K638Del, K638R,
639 6 I639F, I639N,
621 7 S621R, S621N, S621R, S621R,
632 7 P632A, P632S,
627 7 F627L, F627fsX, F627X, F627L, F627L,
637 8 E637K, E637G, E637X,
617 8 F617L, F617V, F617L, F617L,
619 8
620 9 S620G, S620I,
568 9 W568C, W568C,
646 9
618 9 T618S, T618S,
636 9
625 9 V625E,
631 9 S631F,
615 10 L615V, L615F,
622 10 L622F,
564 10 L564L,
620 10 S620G, S620I,
647 10
612 10 V612L, V612L, V612A,
623 10 T623I,
648 10 G648A,
634 10 T634P, T634A, T634S, T634S, T634I,
626 10 G626S, G626A, G626V,
613 11 T613A, T613L, T613K, T613M,
635 11 N635I,
629 11 N629D, N629T, N629S, N629I, N629K, N629K,
630 11 V630I, V630T, V630A,
633 11 N633D, N633S, N633I,
626 11 G626S, G626A, G626V,
571 11 I571L, I571V,
617 11 F617L, F617V, F617L, F617L,
567 11 I567T, I567M,
618 12 T618S, T618S,
624 12 S624R, S624N, S624R, S624R,
649 12
614 12 A614T, A614V,
630 12 V630I, V630T, V630A,
585 12 W585C, W585C,
628 12 G628S, G628R, G628Del, G628D, G628A, G628V,
565 12
621 12 S621R, S621N, S621R, S621R,
614 12 A614T, A614V,
624 12 S624R, S624N, S624R, S624R,
623 12 T623I,
625 13 V625E,
622 13 L622F,
561 13 A561T, A561P, A561V,
628 13 G628S, G628R, G628Del, G628D, G628A, G628V,
619 13
611 14 Y611D,
561 14 A561T, A561P, A561V,
616 14 Y616S,
557 14
609 14 D609N, D609G,
627 14 F627L, F627fsX, F627X, F627L, F627L,
558 14 A558P, A558E, A558V,
615 14 L615V, L615F,
584 14 G584S, G584R, G584C,
570 14
560 14 I560fsX, I560M,
572 14 G572S, G572R, G572C, G572D,
650 14 L650X,
613 15 T613A, T613L, T613K, T613M,
625 15 V625E,
566 15 C566S, C566R, C566G, C566S, C566F,
651 15 M651K
565 15