KCNH2 Variant F656L

Summary of observed carriers, functional annotations, and structural context for KCNH2 F656L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

28%

3/14 effective observations

Total carriers

4

2 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

F656L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 111% of WT with a standard error of 9%. 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 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.815 1.0 0 0.941 52

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
30244407 2018 4 2 2
Literature, cohort, and gnomAD – 4 2 2 –
Variant features alone – 10 9 1 –

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 F656L.
Neighbour residue Distance (Å) Observed variants
656 0 F656L, F656L, F656L,
655 4
652 5 Y652X,
659 5
657 6 G657S, G657V,
649 6
653 6
653 7
654 7
650 7 L650X,
660 7 S660L,
658 7
554 7
557 8
651 8 M651K,
553 8 L553V,
654 9
648 9 G648A,
623 10 T623I,
550 10
646 10
652 10 Y652X,
661 10 A661V,
648 10 G648A,
622 10 L622F,
662 10
556 10
650 11 L650X,
651 11 M651K,
663 11
649 11
660 11 S660L,
647 11
657 12 G657S, G657V,
555 12
558 12 A558P, A558E, A558V,
624 12 S624R, S624N, S624R, S624R,
560 12 I560fsX, I560M,
619 12
549 12 V549M,
645 12 M645L, M645V, M645L, M645R, M645I, M645I, M645I,
552 12 L552S,
655 13
656 13 F656L, F656L, F656L,
656 13 F656L, F656L, F656L,
647 13
652 13 Y652X,
664 13 Q664X,
624 13 S624R, S624N, S624R, S624R,
663 13
551 13 F551L, F551L, F551L,
657 14 G657S, G657V,
664 14 Q664X,
659 14
622 14 L622F,
561 14 A561T, A561P, A561V,
658 14
621 14 S621R, S621N, S621R, S621R,
644 14 V644I, V644F,
559 14 L559F, L559H,
623 15 T623I,
620 15 S620G, S620I,
625 15 V625E,
661 15 A661V,
547 15 A547T,
665 15 R665Q