KCNH2 Variant L586V Detail

We estimate the penetrance of LQTS for KCNH2 L586V is 75%. We are unaware of any observations of this variant in individuals. L586V is not present in gnomAD. L586V has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L586V around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.845 0.859 1 0.831 86
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 3 7 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

L586V has 58 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: 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 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

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