KCNH2 Variant N635K Detail

We estimate the penetrance of LQTS for KCNH2 N635K is 81%. We are unaware of any observations of this variant in individuals. N635K is not present in gnomAD. N635K 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 N635K around 81% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.667 0.88 0 0.818 91
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.

N635K has 52 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
635 0 N635I,
634 4 T634P, T634I, T634S, T634A, T634S,
636 5
638 5 K638R, K638Del, K638D, K638E,
609 6 D609N, D609G,
612 6 V612L, V612A, V612L,
608 6
639 7 I639N, I639F,
637 7 E637K, E637G, E637X,
633 8 N633I, N633D, N633S,
613 8 T613A, T613K, T613M, T613L,
606 9 S606Del, S606P, S606F,
632 9 P632A, P632S,
593 9 I593R, I593V, I593T, I593X, I593K,
616 10 Y616S,
575 10 E575K,
611 10 Y611D,
610 10
571 11 I571V, I571L,
607 11
584 11 G584C, G584R, G584S,
641 11 S641P, S641F,
589 11 L589P,
642 11 I642V, I642Del,
640 11 F640L, F640Del, F640L, F640V, F640L,
614 11 A614V, A614T,
583 11 I583V,
615 11 L615V, L615F,
605 11 P605L,
592 12 Q592X,
595 12 K595N, K595N, K595E,
629 12 N629T, N629I, N629S, N629D, N629K, N629K,
594 12
631 12 S631F,
572 12 G572D, G572S, G572R, G572C,
568 13 W568C, W568C,
585 13 W585C, W585C,
630 13 V630A, V630I, V630T,
590 13 G590V, G590D,
643 13
577 13
604 14 G604C, G604D, G604S,
627 14 F627X, F627L, F627L, F627fsX, F627L,
617 14 F617V, F617L, F617L, F617L,
570 14
586 15 L586M,
585 15 W585C, W585C,
576 15
574 15 M574V, M574L, M574L,
619 15
565 15
645 15 M645R, M645L, M645I, M645V, M645I, M645L, M645I,