KCNH2 Variant S636A Detail

We estimate the penetrance of LQTS for KCNH2 S636A is 78%. We are unaware of any observations of this variant in individuals. S636A is not present in gnomAD. S636A 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 S636A around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.466 0.043 1 0.665 90
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.

S636A has 55 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
636 0
637 4 E637G, E637X, E637K,
634 5 T634A, T634S, T634S, T634P, T634I,
635 5 N635I,
639 5 I639F, I639N,
571 6 I571L, I571V,
638 6 K638R, K638Del, K638E, K638D,
640 7 F640L, F640L, F640V, F640Del, F640L,
575 7 E575K,
632 8 P632S, P632A,
568 9 W568C, W568C,
572 9 G572C, G572S, G572D, G572R,
633 9 N633I, N633D, N633S,
641 9 S641P, S641F,
612 9 V612A, V612L, V612L,
570 10
608 10
584 10 G584R, G584C, G584S,
642 10 I642V, I642Del,
609 10 D609G, D609N,
585 10 W585C, W585C,
616 11 Y616S,
567 11 I567T, I567M,
643 11
574 11 M574V, M574L, M574L,
613 11 T613L, T613M, T613A, T613K,
583 12 I583V,
631 12 S631F,
573 12
644 12 V644I, V644F,
593 12 I593V, I593K, I593X, I593T, I593R,
576 13
617 13 F617V, F617L, F617L, F617L,
577 13
615 13 L615F, L615V,
586 13 L586M,
569 13 Y569H, Y569C, Y569X,
611 13 Y611D,
564 13 L564L,
629 13 N629T, N629K, N629D, N629S, N629K, N629I,
606 13 S606P, S606F, S606Del,
645 14 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
565 14
630 14 V630A, V630I, V630T,
627 14 F627L, F627fsX, F627L, F627X, F627L,
614 14 A614T, A614V,
592 14 Q592X,
587 14
618 15 T618S, T618S,
614 15 A614T, A614V,
589 15 L589P,
566 15 C566S, C566F, C566G, C566R, C566S,
621 15 S621R, S621R, S621R, S621N,
610 15
588 15 N588D, N588K, N588K,