KCNH2 Variant E637Q Detail

We estimate the penetrance of LQTS for KCNH2 E637Q is 78%. We are unaware of any observations of this variant in individuals. E637Q is not present in gnomAD. E637Q 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 E637Q around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.9 0.999 2 0.872 93
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.

E637Q has 65 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
637 0 E637K, E637G, E637X,
634 4 T634P, T634I, T634S, T634A, T634S,
636 4
632 5 P632A, P632S,
638 5 K638R, K638Del, K638D, K638E,
633 6 N633I, N633D, N633S,
568 6 W568C, W568C,
571 6 I571V, I571L,
635 7 N635I,
640 7 F640L, F640Del, F640L, F640V, F640L,
585 7 W585C, W585C,
584 7 G584C, G584R, G584S,
639 7 I639N, I639F,
631 7 S631F,
641 8 S641P, S641F,
572 8 G572D, G572S, G572R, G572C,
575 9 E575K,
616 9 Y616S,
617 9 F617V, F617L, F617L, F617L,
630 10 V630A, V630I, V630T,
583 10 I583V,
570 10
586 10 L586M,
629 10 N629T, N629I, N629S, N629D, N629K, N629K,
642 10 I642V, I642Del,
612 10 V612L, V612A, V612L,
567 11 I567M, I567T,
627 11 F627X, F627L, F627L, F627fsX, F627L,
613 11 T613A, T613K, T613M, T613L,
588 11 N588K, N588K, N588D,
573 11
644 11 V644F, V644I,
593 11 I593R, I593V, I593T, I593X, I593K,
569 12 Y569C, Y569X, Y569H,
643 12
614 12 A614V, A614T,
609 12 D609N, D609G,
592 12 Q592X,
587 12
565 12
618 12 T618S, T618S,
574 12 M574V, M574L, M574L,
564 12 L564L,
621 12 S621R, S621R, S621N, S621R,
576 12
645 13 M645R, M645L, M645I, M645V, M645I, M645L, M645I,
613 13 T613A, T613K, T613M, T613L,
608 13
628 13 G628R, G628D, G628V, G628A, G628S, G628Del,
589 13 L589P,
628 13 G628R, G628D, G628V, G628A, G628S, G628Del,
577 13
630 13 V630A, V630I, V630T,
589 14 L589P,
615 14 L615V, L615F,
566 14 C566S, C566F, C566S, C566G, C566R,
620 14 S620I, S620G,
614 14 A614V, A614T,
629 14 N629T, N629I, N629S, N629D, N629K, N629K,
620 14 S620I, S620G,
616 15 Y616S,
610 15
626 15 G626S, G626V, G626A,
626 15 G626S, G626V, G626A,
619 15