KCNH2 Variant F640L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F640L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

46%

5/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F640L 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 (%)
-5.801 0.93 0 0.914 91

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
19038855 2009 1 0 1 Seizure
10220144 1999 1 0 1
Literature, cohort, and gnomAD – 2 0 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 F640L.
Neighbour residue Distance (Å) Observed variants
640 0 F640L, F640V, F640Del, F640L, F640L,
641 5 S641P, S641F,
643 5
644 6 V644I, V644F,
568 6 W568C, W568C,
639 6 I639F, I639N,
564 7 L564L,
567 7 I567T, I567M,
637 7 E637K, E637G, E637X,
642 7 I642V, I642Del,
636 7
571 8 I571L, I571V,
617 8 F617L, F617V, F617L, F617L,
618 8 T618S, T618S,
638 8 K638E, K638D, K638Del, K638R,
645 9 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
632 9 P632A, P632S,
621 9 S621R, S621N, S621R, S621R,
565 9
647 10
570 10
634 10 T634P, T634A, T634S, T634S, T634I,
616 10 Y616S,
646 11
614 11 A614T, A614V,
622 11 L622F,
566 11 C566S, C566R, C566G, C566S, C566F,
585 11 W585C, W585C,
561 11 A561T, A561P, A561V,
635 11 N635I,
631 11 S631F,
572 11 G572S, G572R, G572C, G572D,
627 11 F627L, F627fsX, F627X, F627L, F627L,
648 12 G648A,
620 12 S620G, S620I,
630 12 V630I, V630T, V630A,
569 12 Y569H, Y569C, Y569X,
612 12 V612L, V612L, V612A,
560 12 I560fsX, I560M,
633 12 N633D, N633S, N633I,
619 12
563 13 W563G, W563C, W563C, W563X,
615 13 L615V, L615F,
575 13 E575K,
615 13 L615V, L615F,
619 13
620 13 S620G, S620I,
625 13 V625E,
562 14 H562P, H562R, H562Q, H562Q,
613 14 T613A, T613L, T613K, T613M,
584 14 G584S, G584R, G584C,
574 14 M574L, M574V, M574L,
649 14
613 14 T613A, T613L, T613K, T613M,
573 14
629 14 N629D, N629T, N629S, N629I, N629K, N629K,
616 14 Y616S,
623 14 T623I,
626 14 G626S, G626A, G626V,
623 14 T623I,
586 14 L586M,
624 15 S624R, S624N, S624R, S624R,
626 15 G626S, G626A, G626V,
651 15 M651K