KCNH2 Variant L586R Detail

We estimate the penetrance of LQTS for KCNH2 L586R is 80%. We are unaware of any observations of this variant in individuals. L586R is not present in gnomAD. L586R 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L586R around 80% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.691 0.998 -2 0.965 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 2 8 -
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.

L586R 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 G572S, G572C, G572R, G572D,
584 6 G584S, G584C, G584R,
610 7
588 7 N588K, N588K, N588D,
590 7 G590V, G590D,
573 8
605 8 P605L,
569 8 Y569X, Y569C, Y569H,
597 8 Y597C, Y597H,
576 8
568 9 W568C, W568C,
613 9 T613K, T613M, T613L, T613A,
583 9 I583V,
604 10 G604C, G604S, G604D,
571 10 I571L, I571V,
591 10 D591N, D591H,
609 10 D609N, D609G,
614 10 A614T, A614V,
630 10 V630I, V630A, V630T,
570 10
637 10 E637X, E637K, E637G,
592 10 Q592X,
593 10 I593K, I593T, I593X, I593R, I593V,
606 11 S606F, S606Del, S606P,
595 11 K595E, K595N, K595N,
596 11 P596S, P596T, P596R, P596L,
631 11 S631F,
575 11 E575K,
607 11
633 11 N633S, N633I, N633D,
603 11 G603D,
634 11 T634P, T634S, T634I, T634S, T634A,
577 12
632 12 P632S, P632A,
431 12 F431L, F431L, F431L,
617 12 F617L, F617L, F617V, F617L,
574 12 M574L, M574V, M574L,
594 12
612 12 V612A, V612L, V612L,
565 13
629 13 N629K, N629I, N629T, N629S, N629K, N629D,
611 13 Y611D,
636 13
566 13 C566F, C566S, C566R, C566S, C566G,
430 14
616 14 Y616S,
567 14 I567T, I567M,
633 14 N633S, N633I, N633D,
638 14 K638E, K638R, K638D, K638Del,
615 14 L615F, L615V,
608 14
628 14 G628Del, G628D, G628V, G628R, G628S, G628A,
640 14 F640Del, F640L, F640L, F640L, F640V,
635 15 N635I,