KCNH2 Variant L589Q Detail

We estimate the penetrance of LQTS for KCNH2 L589Q is 72%. We are unaware of any observations of this variant in individuals. L589Q is not present in gnomAD. L589Q 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 L589Q around 72% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.691 1.0 -2 0.947 76
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.

L589Q has 59 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
589 0 L589P,
590 4 G590D, G590V,
592 5 Q592X,
588 5 N588K, N588D, N588K,
593 5 I593R, I593K, I593V, I593T, I593X,
586 6 L586M,
591 6 D591N, D591H,
585 7 W585C, W585C,
605 7 P605L,
613 7 T613L, T613A, T613K, T613M,
587 8
595 8 K595E, K595N, K595N,
610 8
609 8 D609G, D609N,
630 8 V630A, V630T, V630I,
594 8
633 9 N633I, N633D, N633S,
629 9 N629D, N629I, N629K, N629K, N629S, N629T,
584 9 G584S, G584C, G584R,
596 9 P596S, P596R, P596L, P596T,
606 9 S606F, S606P, S606Del,
597 10 Y597H, Y597C,
604 10 G604S, G604C, G604D,
631 10 S631F,
614 10 A614T, A614V,
638 11 K638E, K638Del, K638R, K638D,
612 11 V612A, V612L, V612L,
635 11 N635I,
634 11 T634S, T634I, T634S, T634A, T634P,
616 11 Y616S,
569 11 Y569H, Y569C, Y569X,
568 11 W568C, W568C,
632 11 P632A, P632S,
628 12 G628D, G628A, G628S, G628V, G628Del, G628R,
572 12 G572D, G572R, G572C, G572S,
607 12
583 12 I583V,
617 12 F617L, F617L, F617V, F617L,
583 12 I583V,
603 12 G603D,
633 13 N633I, N633D, N633S,
608 13
573 13
631 13 S631F,
632 13 P632A, P632S,
584 13 G584S, G584C, G584R,
637 13 E637G, E637X, E637K,
611 13 Y611D,
637 14 E637G, E637X, E637K,
576 14
615 14 L615F, L615V,
571 14 I571V, I571L,
565 14
627 14 F627fsX, F627L, F627L, F627L, F627X,
634 15 T634S, T634I, T634S, T634A, T634P,
629 15 N629D, N629I, N629K, N629K, N629S, N629T,
636 15
431 15 F431L, F431L, F431L,
570 15