KCNH2 Variant T618S Detail

We estimate the penetrance of LQTS for KCNH2 T618S is 55%. This variant was found in a total of 6 carriers in 1 papers or gnomAD, 3 had LQTS. T618S is not present in gnomAD. T618S 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 T618S around 55% (8/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.794 0.873 1 0.909 68
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
Japan Cohort 2020 6 3 3
LITERATURE, COHORT, AND GNOMAD: - 6 3 3 -
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.

T618S has 83 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
618 0 T618S, T618S,
617 4 F617V, F617L, F617L, F617L,
619 5
561 5 A561V, A561P, A561T,
564 5 L564L,
621 5 S621N, S621R, S621R, S621R,
615 5 L615V, L615F,
622 6 L622F,
620 6 S620I, S620G,
565 6
614 6 A614T, A614V,
644 7 V644F, V644I,
568 8 W568C, W568C,
616 8 Y616S,
640 8 F640L, F640V, F640L, F640L, F640Del,
623 8 T623I,
560 8 I560fsX, I560M,
641 9 S641F, S641P,
562 9 H562Q, H562Q, H562R, H562P,
613 9 T613A, T613L, T613K, T613M,
642 9 I642Del, I642V,
567 9 I567M, I567T,
558 9 A558V, A558P, A558E,
557 9
566 9 C566G, C566S, C566R, C566F, C566S,
645 9 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
630 10 V630I, V630T, V630A,
648 10 G648A,
611 10 Y611D,
645 10 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
612 10 V612L, V612A, V612L,
625 10 V625E,
647 10
626 11 G626A, G626S, G626V,
563 11 W563X, W563C, W563G, W563C,
643 11
624 11 S624R, S624R, S624R, S624N,
627 11 F627X, F627L, F627fsX, F627L, F627L,
627 11 F627X, F627L, F627fsX, F627L, F627L,
559 11 L559F, L559H,
641 12 S641F, S641P,
585 12 W585C, W585C,
625 12 V625E,
631 12 S631F,
638 12 K638Del, K638E, K638D, K638R,
646 12
632 12 P632S, P632A,
651 12 M651K,
637 12 E637G, E637X, E637K,
642 12 I642Del, I642V,
569 12 Y569H, Y569C, Y569X,
571 13 I571V, I571L,
652 13 Y652X,
628 13 G628V, G628R, G628A, G628D, G628Del, G628S,
649 13
570 13
629 13 N629K, N629S, N629K, N629I, N629D, N629T,
639 13 I639F, I639N,
646 13
556 13
626 14 G626A, G626S, G626V,
649 14
632 14 P632S, P632A,
610 14
623 14 T623I,
643 14
609 14 D609N, D609G,
639 14 I639F, I639N,
644 14 V644F, V644I,
638 14 K638Del, K638E, K638D, K638R,
624 14 S624R, S624R, S624R, S624N,
616 14 Y616S,
621 14 S621N, S621R, S621R, S621R,
620 14 S620I, S620G,
426 14 P426H,
624 15 S624R, S624R, S624R, S624N,
636 15
431 15 F431L, F431L, F431L,
423 15
554 15
572 15 G572S, G572R, G572C, G572D,
650 15 L650X,
626 15 G626A, G626S, G626V,