KCNH2 Variant S621T Detail

We estimate the penetrance of LQTS for KCNH2 S621T is 65%. We are unaware of any observations of this variant in individuals. S621T is not present in gnomAD. S621T 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S621T around 65% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.925 0.597 1 0.794 75
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 4 6 -
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.

S621T has 90 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
621 0 S621N, S621R, S621R, S621R,
620 4 S620I, S620G,
622 5 L622F,
618 5 T618S, T618S,
644 5 V644F, V644I,
617 6 F617V, F617L, F617L, F617L,
645 6 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
623 6 T623I,
624 6 S624R, S624R, S624R, S624N,
625 6 V625E,
641 7 S641F, S641P,
626 7 G626A, G626S, G626V,
625 7 V625E,
627 7 F627X, F627L, F627fsX, F627L, F627L,
619 7
648 8 G648A,
626 9 G626A, G626S, G626V,
640 9 F640L, F640V, F640L, F640L, F640Del,
623 9 T623I,
620 9 S620I, S620G,
564 9 L564L,
616 9 Y616S,
624 9 S624R, S624R, S624R, S624N,
627 9 F627X, F627L, F627fsX, F627L, F627L,
645 9 M645L, M645I, M645I, M645L, M645I, M645V, M645R,
642 10 I642Del, I642V,
647 10
561 10 A561V, A561P, A561T,
643 10
649 10
630 10 V630I, V630T, V630A,
568 10 W568C, W568C,
632 10 P632S, P632A,
615 10 L615V, L615F,
652 10 Y652X,
646 10
624 10 S624R, S624R, S624R, S624N,
631 11 S631F,
616 11 Y616S,
614 11 A614T, A614V,
565 11
628 11 G628V, G628R, G628A, G628D, G628Del, G628S,
619 11
557 11
626 11 G626A, G626S, G626V,
560 11 I560fsX, I560M,
642 12 I642Del, I642V,
651 12 M651K,
625 12 V625E,
638 12 K638Del, K638E, K638D, K638R,
625 12 V625E,
637 12 E637G, E637X, E637K,
641 12 S641F, S641P,
613 12 T613A, T613L, T613K, T613M,
621 13 S621N, S621R, S621R, S621R,
621 13 S621N, S621R, S621R, S621R,
628 13 G628V, G628R, G628A, G628D, G628Del, G628S,
626 13 G626A, G626S, G626V,
624 13 S624R, S624R, S624R, S624N,
649 13
629 13 N629K, N629S, N629K, N629I, N629D, N629T,
629 13 N629K, N629S, N629K, N629I, N629D, N629T,
639 13 I639F, I639N,
650 13 L650X,
622 13 L622F,
567 13 I567M, I567T,
646 13
558 13 A558V, A558P, A558E,
652 13 Y652X,
585 14 W585C, W585C,
617 14 F617V, F617L, F617L, F617L,
638 14 K638Del, K638E, K638D, K638R,
627 14 F627X, F627L, F627fsX, F627L, F627L,
653 14
648 14 G648A,
562 14 H562Q, H562Q, H562R, H562P,
644 14 V644F, V644I,
618 14 T618S, T618S,
620 14 S620I, S620G,
632 14 P632S, P632A,
656 14 F656L, F656L, F656L,
612 14 V612L, V612A, V612L,
566 14 C566G, C566S, C566R, C566F, C566S,
623 15 T623I,
630 15 V630I, V630T, V630A,
615 15 L615V, L615F,
636 15
633 15 N633D, N633I, N633S,
563 15 W563X, W563C, W563G, W563C,
571 15 I571V, I571L,