KCNH2 Variant L586M

Summary of observed carriers, functional annotations, and structural context for KCNH2 L586M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

41%

6/13 effective observations

Total carriers

3

3 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L586M 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 2%. 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 (%)
-1.897 0.999 2 0.791 86

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
Italy Cohort 2020 2 0 2
22402334 2012 1 0 1
Literature, cohort, and gnomAD – 3 0 3 –
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 L586M.
Neighbour residue Distance (Å) Observed variants
586 0 L586M,
585 4 W585C, W585C,
587 5
589 6 L589P,
572 6 G572S, G572R, G572C, G572D,
584 6 G584S, G584R, G584C,
610 7
588 7 N588D, N588K, N588K,
590 7 G590D, G590V,
573 8
605 8 P605L,
569 8 Y569H, Y569C, Y569X,
597 8 Y597H, Y597C,
576 8
568 9 W568C, W568C,
613 9 T613A, T613L, T613K, T613M,
583 9 I583V,
604 10 G604S, G604C, G604D,
571 10 I571L, I571V,
591 10 D591N, D591H,
609 10 D609N, D609G,
614 10 A614T, A614V,
630 10 V630I, V630T, V630A,
570 10
637 10 E637K, E637G, E637X,
592 10 Q592X,
593 10 I593V, I593K, I593T, I593R, I593X,
606 11 S606Del, S606P, S606F,
595 11 K595E, K595N, K595N,
596 11 P596T, P596S, P596R, P596L,
631 11 S631F,
575 11 E575K,
607 11
633 11 N633D, N633S, N633I,
603 11 G603D,
634 11 T634P, T634A, T634S, T634S, T634I,
577 12
632 12 P632A, P632S,
431 12 F431L, F431L, F431L,
617 12 F617L, F617V, F617L, F617L,
574 12 M574L, M574V, M574L,
594 12
612 12 V612L, V612L, V612A,
565 13
629 13 N629D, N629T, N629S, N629I, N629K, N629K,
611 13 Y611D,
636 13
566 13 C566S, C566R, C566G, C566S, C566F,
430 14
616 14 Y616S,
567 14 I567T, I567M,
633 14 N633D, N633S, N633I,
638 14 K638E, K638D, K638Del, K638R,
615 14 L615V, L615F,
608 14
628 14 G628S, G628R, G628Del, G628D, G628A, G628V,
640 14 F640L, F640V, F640Del, F640L, F640L
635 15 N635I,