KCNH2 Variant T613S Detail

We estimate the penetrance of LQTS for KCNH2 T613S is 79%. We are unaware of any observations of this variant in individuals. T613S is not present in gnomAD. T613S 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 T613S around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.744 0.873 1 0.83 92
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.

T613S has 74 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
613 0 T613K, T613M, T613L, T613A,
614 4 A614T, A614V,
612 4 V612A, V612L, V612L,
616 5 Y616S,
609 6 D609G, D609N,
638 6 K638E, K638R, K638D, K638Del,
615 7 L615F, L615V,
630 7 V630I, V630A, V630T,
610 7
617 7 F617L, F617L, F617V, F617L,
611 7 Y611D,
589 7 L589P,
585 7 W585C, W585C,
635 8 N635I,
568 8 W568C, W568C,
565 9
629 9 N629K, N629I, N629T, N629S, N629K, N629D,
586 9 L586M,
632 9 P632S, P632A,
633 9 N633S, N633I, N633D,
618 9 T618S, T618S,
569 10 Y569X, Y569C, Y569H,
608 10
634 10 T634P, T634S, T634I, T634S, T634A,
639 10 I639N, I639F,
592 10 Q592X,
606 10 S606F, S606Del, S606P,
593 10 I593K, I593T, I593X, I593R, I593V,
642 10 I642V, I642Del,
607 10
620 10 S620G, S620I,
631 10 S631F,
605 11 P605L,
588 11 N588K, N588K, N588D,
641 11 S641P, S641F,
619 11
628 11 G628Del, G628D, G628V, G628R, G628S, G628A,
627 11 F627L, F627L, F627fsX, F627X, F627L,
566 11 C566F, C566S, C566R, C566S, C566G,
637 11 E637X, E637K, E637G,
636 11
590 12 G590V, G590D,
431 12 F431L, F431L, F431L,
561 12 A561V, A561T, A561P,
631 12 S631F,
562 12 H562P, H562Q, H562Q, H562R,
564 12 L564L,
572 12 G572S, G572C, G572R, G572D,
621 12 S621R, S621R, S621R, S621N,
632 13 P632S, P632A,
645 13 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
584 13 G584S, G584C, G584R,
626 13 G626V, G626A, G626S,
595 13 K595E, K595N, K595N,
637 13 E637X, E637K, E637G,
570 13
567 13 I567T, I567M,
571 13 I571L, I571V,
427 13 Y427C, Y427S, Y427H,
587 14
573 14
591 14 D591N, D591H,
640 14 F640Del, F640L, F640L, F640L, F640V,
640 14 F640Del, F640L, F640L, F640L, F640V,
627 14 F627L, F627L, F627fsX, F627X, F627L,
604 14 G604C, G604S, G604D,
594 14
625 14 V625E,
622 14 L622F,
430 14
641 15 S641P, S641F,
584 15 G584S, G584C, G584R,
633 15 N633S, N633I, N633D,
643 15