KCNH2 Variant A565S Detail

We estimate the penetrance of LQTS for KCNH2 A565S is 53%. We are unaware of any observations of this variant in individuals. A565S is not present in gnomAD. A565S 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A565S around 53% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.875 0.999 1 0.911 64
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 5 5 -
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.

A565S has 69 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
565 0
566 4 C566S, C566F, C566G, C566R, C566S,
564 5 L564L,
614 5 A614T, A614V,
567 6 I567T, I567M,
615 6 L615F, L615V,
562 6 H562R, H562Q, H562Q, H562P,
561 6 A561V, A561T, A561P,
618 6 T618S, T618S,
568 6 W568C, W568C,
611 6 Y611D,
569 7 Y569H, Y569C, Y569X,
617 8 F617V, F617L, F617L, F617L,
563 8 W563C, W563X, W563G, W563C,
570 9
613 9 T613L, T613M, T613A, T613K,
431 9 F431L, F431L, F431L,
612 9 V612A, V612L, V612L,
640 9 F640L, F640L, F640V, F640Del, F640L,
426 9 P426H,
619 9
430 9
560 9 I560fsX, I560M,
571 10 I571L, I571V,
427 10 Y427H, Y427C, Y427S,
610 10
585 10 W585C, W585C,
558 10 A558E, A558V, A558P,
559 10 L559H, L559F,
616 10 Y616S,
644 11 V644I, V644F,
423 11
621 11 S621R, S621R, S621R, S621N,
622 11 L622F,
572 11 G572C, G572S, G572D, G572R,
620 11 S620G, S620I,
609 12 D609G, D609N,
429 12 A429V, A429P,
630 12 V630A, V630I, V630T,
642 12 I642V, I642Del,
573 12
637 12 E637G, E637X, E637K,
641 12 S641P, S641F,
422 12 A422T,
607 12
586 13 L586M,
557 13
643 13
428 13 S428X, S428L, S428fsX,
425 13
638 13 K638R, K638Del, K638E, K638D,
608 13
424 13
647 14
632 14 P632S, P632A,
574 14 M574V, M574L, M574L,
631 14 S631F,
636 14
639 14 I639F, I639N,
623 14 T623I,
645 14 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
432 14
589 14 L589P,
556 14
648 15 G648A,
606 15 S606P, S606F, S606Del,
645 15 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
635 15 N635I,
641 15 S641P, S641F,