KCNH2 Variant N633K Detail

We estimate the penetrance of LQTS for KCNH2 N633K is 79%. We are unaware of any observations of this variant in individuals. N633K is not present in gnomAD. N633K 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 N633K around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.759 0.887 0 0.909 89
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.

N633K has 64 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
633 0 N633D, N633I, N633S,
632 5 P632A, P632S,
634 5 T634P, T634I, T634S, T634A, T634S,
584 6 G584S, G584R, G584C,
631 6 S631F,
592 6 Q592X,
637 6 E637G, E637X, E637K,
629 6 N629T, N629K, N629D, N629I, N629K, N629S,
638 6 K638E, K638D, K638Del, K638R,
593 7 I593R, I593V, I593X, I593T, I593K,
583 7 I583V,
635 8 N635I,
588 9 N588K, N588K, N588D,
589 9 L589P,
585 9 W585C, W585C,
636 9
616 9 Y616S,
613 9 T613M, T613A, T613K, T613L,
630 9 V630A, V630I, V630T,
630 10 V630A, V630I, V630T,
628 10 G628D, G628V, G628Del, G628S, G628A, G628R,
627 10 F627L, F627L, F627fsX, F627L, F627X,
609 10 D609N, D609G,
594 11
590 11 G590V, G590D,
612 11 V612L, V612A, V612L,
587 11
568 11 W568C, W568C,
641 11 S641P, S641F,
588 11 N588K, N588K, N588D,
628 11 G628D, G628V, G628Del, G628S, G628A, G628R,
591 11 D591H, D591N,
586 11 L586M,
639 11 I639F, I639N,
572 12 G572D, G572R, G572C, G572S,
571 12 I571L, I571V,
595 12 K595N, K595N, K595E,
617 12 F617L, F617V, F617L, F617L,
575 12 E575K,
640 12 F640Del, F640L, F640L, F640L, F640V,
589 13 L589P,
629 13 N629T, N629K, N629D, N629I, N629K, N629S,
631 13 S631F,
614 13 A614V, A614T,
606 13 S606Del, S606P, S606F,
605 13 P605L,
642 13 I642V, I642Del,
585 13 W585C, W585C,
617 13 F617L, F617V, F617L, F617L,
591 13 D591H, D591N,
610 13
577 14
592 14 Q592X,
608 14
626 14 G626S, G626V, G626A,
586 14 L586M,
576 14
615 14 L615F, L615V,
620 14 S620G, S620I,
590 14 G590V, G590D,
626 15 G626S, G626V, G626A,
613 15 T613M, T613A, T613K, T613L,
621 15 S621R, S621R, S621R, S621N,
614 15 A614V, A614T,