KCNH2 Variant K638Q Detail

We estimate the penetrance of LQTS for KCNH2 K638Q is 77%. We are unaware of any observations of this variant in individuals. K638Q is not present in gnomAD. K638Q 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 K638Q around 77% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.862 0.997 1 0.808 88
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.

K638Q has 72 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
638 0 K638R, K638Del, K638E, K638D,
616 5 Y616S,
632 5 P632S, P632A,
635 5 N635I,
637 5 E637G, E637X, E637K,
634 6 T634A, T634S, T634S, T634P, T634I,
612 6 V612A, V612L, V612L,
639 6 I639F, I639N,
613 6 T613L, T613M, T613A, T613K,
641 6 S641P, S641F,
636 6
633 6 N633I, N633D, N633S,
642 7 I642V, I642Del,
609 8 D609G, D609N,
629 8 N629T, N629K, N629D, N629S, N629K, N629I,
640 8 F640L, F640L, F640V, F640Del, F640L,
615 8 L615F, L615V,
631 8 S631F,
614 9 A614T, A614V,
627 9 F627L, F627fsX, F627L, F627X, F627L,
630 9 V630A, V630I, V630T,
611 10 Y611D,
608 10
645 10 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
617 10 F617V, F617L, F617L, F617L,
568 11 W568C, W568C,
593 11 I593V, I593K, I593X, I593T, I593R,
620 11 S620G, S620I,
589 11 L589P,
592 11 Q592X,
643 11
619 11
584 11 G584R, G584C, G584S,
571 11 I571L, I571V,
628 11 G628R, G628Del, G628S, G628V, G628D, G628A,
644 11 V644I, V644F,
617 12 F617V, F617L, F617L, F617L,
610 12
585 12 W585C, W585C,
618 12 T618S, T618S,
630 12 V630A, V630I, V630T,
621 12 S621R, S621R, S621R, S621N,
606 12 S606P, S606F, S606Del,
626 12 G626S, G626A, G626V,
583 13 I583V,
575 13 E575K,
585 13 W585C, W585C,
625 13 V625E,
565 13
572 13 G572C, G572S, G572D, G572R,
631 13 S631F,
628 14 G628R, G628Del, G628S, G628V, G628D, G628A,
607 14
646 14
568 14 W568C, W568C,
588 14 N588D, N588K, N588K,
605 14 P605L,
621 14 S621R, S621R, S621R, S621N,
590 14 G590D, G590V,
626 14 G626S, G626A, G626V,
561 14 A561V, A561T, A561P,
588 14 N588D, N588K, N588K,
618 14 T618S, T618S,
586 14 L586M,
623 14 T623I,
567 14 I567T, I567M,
595 15 K595N, K595N, K595E,
620 15 S620G, S620I,
594 15
564 15 L564L,
570 15
562 15 H562R, H562Q, H562Q, H562P,