KCNH2 Variant K610N Detail

We estimate the penetrance of LQTS for KCNH2 K610N is 78%. We are unaware of any observations of this variant in individuals. K610N is not present in gnomAD. K610N 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 K610N around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.667 0.997 0 0.841 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.

K610N has 60 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
610 0
609 5 D609N, D609G,
607 5
606 5 S606Del, S606P, S606F,
605 6 P605L,
569 6 Y569C, Y569X, Y569H,
613 7 T613A, T613K, T613M, T613L,
586 7 L586M,
431 7 F431L, F431L, F431L,
611 7 Y611D,
612 8 V612L, V612A, V612L,
614 8 A614V, A614T,
608 8
589 8 L589P,
585 8 W585C, W585C,
604 9 G604C, G604D, G604S,
573 9
572 10 G572D, G572S, G572R, G572C,
565 10
635 10 N635I,
595 10 K595N, K595N, K595E,
568 10 W568C, W568C,
566 10 C566S, C566F, C566S, C566G, C566R,
427 10 Y427S, Y427C, Y427H,
430 10
593 10 I593R, I593V, I593T, I593X, I593K,
590 10 G590V, G590D,
570 11
615 11 L615V, L615F,
597 11 Y597C, Y597H,
603 11 G603D,
432 12
587 12
638 12 K638R, K638Del, K638D, K638E,
588 12 N588K, N588K, N588D,
616 12 Y616S,
571 12 I571V, I571L,
630 12 V630A, V630I, V630T,
592 12 Q592X,
617 13 F617V, F617L, F617L, F617L,
594 13
584 13 G584C, G584R, G584S,
634 13 T634P, T634I, T634S, T634A, T634S,
567 13 I567M, I567T,
596 13 P596T, P596L, P596S, P596R,
576 13
562 13 H562R, H562Q, H562P, H562Q,
633 13 N633I, N633D, N633S,
429 14 A429P, A429V,
428 14 S428L, S428X, S428fsX,
591 14 D591H, D591N,
618 14 T618S, T618S,
639 14 I639N, I639F,
574 14 M574V, M574L, M574L,
426 14 P426H,
629 14 N629T, N629I, N629S, N629D, N629K, N629K,
637 15 E637K, E637G, E637X,
564 15 L564L,
631 15 S631F,
636 15