KCNH2 Variant W585L Detail

We estimate the penetrance of LQTS for KCNH2 W585L is 81%. We are unaware of any observations of this variant in individuals. W585L is not present in gnomAD. W585L 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 W585L around 81% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-12.33 0.999 -2 0.878 87
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.

W585L has 74 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
585 0 W585C, W585C,
586 4 L586M,
568 5 W568C, W568C,
584 6 G584C, G584S, G584R,
572 6 G572S, G572R, G572C, G572D,
589 7 L589P,
637 7 E637G, E637X, E637K,
588 7 N588K, N588K, N588D,
630 7 V630I, V630T, V630A,
631 7 S631F,
613 7 T613A, T613L, T613K, T613M,
614 8 A614T, A614V,
569 8 Y569H, Y569C, Y569X,
571 8 I571V, I571L,
587 8
632 8 P632S, P632A,
610 8
617 8 F617V, F617L, F617L, F617L,
633 9 N633D, N633I, N633S,
573 9
634 9 T634S, T634I, T634S, T634P, T634A,
570 9
583 10 I583V,
590 10 G590D, G590V,
565 10
592 10 Q592X,
636 10
609 11 D609N, D609G,
576 11
629 11 N629K, N629S, N629K, N629I, N629D, N629T,
605 11 P605L,
640 11 F640L, F640V, F640L, F640L, F640Del,
575 11 E575K,
616 11 Y616S,
612 11 V612L, V612A, V612L,
591 11 D591N, D591H,
567 11 I567M, I567T,
628 12 G628V, G628R, G628A, G628D, G628Del, G628S,
618 12 T618S, T618S,
638 12 K638Del, K638E, K638D, K638R,
566 12 C566G, C566S, C566R, C566F, C566S,
593 12 I593X, I593V, I593R, I593K, I593T,
597 12 Y597H, Y597C,
615 12 L615V, L615F,
611 12 Y611D,
641 12 S641F, S641P,
629 12 N629K, N629S, N629K, N629I, N629D, N629T,
574 13 M574V, M574L, M574L,
431 13 F431L, F431L, F431L,
606 13 S606P, S606F, S606Del,
564 13 L564L,
638 13 K638Del, K638E, K638D, K638R,
627 13 F627X, F627L, F627fsX, F627L, F627L,
607 13
635 13 N635I,
604 13 G604S, G604D, G604C,
633 13 N633D, N633I, N633S,
577 13
620 14 S620I, S620G,
595 14 K595N, K595E, K595N,
621 14 S621N, S621R, S621R, S621R,
592 14 Q592X,
430 14
639 14 I639F, I639N,
596 14 P596L, P596S, P596T, P596R,
632 14 P632S, P632A,
616 14 Y616S,
627 14 F627X, F627L, F627fsX, F627L, F627L,
628 15 G628V, G628R, G628A, G628D, G628Del, G628S,
635 15 N635I,
644 15 V644F, V644I,
593 15 I593X, I593V, I593R, I593K, I593T,
626 15 G626A, G626S, G626V,
594 15