KCNH2 Variant S620C Detail

We estimate the penetrance of LQTS for KCNH2 S620C is 79%. We are unaware of any observations of this variant in individuals. S620C is not present in gnomAD. S620C has been functionally characterized in 1 papers. 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 S620C around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.476 0.95 -1 0.847 86
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
9486667 Xeno 125 0 None None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
9486667 Xeno None None None

S620C has 92 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
620 0 S620G, S620I,
621 4 S621R, S621R, S621R, S621N,
625 5 V625E,
626 5 G626V, G626A, G626S,
623 5 T623I,
617 5 F617L, F617L, F617V, F617L,
618 6 T618S, T618S,
619 6
616 6 Y616S,
627 6 F627L, F627L, F627fsX, F627X, F627L,
622 6 L622F,
645 6 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
624 6 S624R, S624N, S624R, S624R,
625 7 V625E,
627 8 F627L, F627L, F627fsX, F627X, F627L,
642 8 I642V, I642Del,
641 9 S641P, S641F,
630 9 V630I, V630A, V630T,
615 9 L615F, L615V,
624 9 S624R, S624N, S624R, S624R,
626 9 G626V, G626A, G626S,
644 9 V644F, V644I,
626 9 G626V, G626A, G626S,
621 9 S621R, S621R, S621R, S621N,
628 9 G628Del, G628D, G628V, G628R, G628S, G628A,
614 10 A614T, A614V,
645 10 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
641 10 S641P, S641F,
561 10 A561V, A561T, A561P,
629 10 N629K, N629I, N629T, N629S, N629K, N629D,
613 10 T613K, T613M, T613L, T613A,
624 10 S624R, S624N, S624R, S624R,
625 10 V625E,
631 11 S631F,
648 11 G648A,
638 11 K638E, K638R, K638D, K638Del,
632 11 P632S, P632A,
644 11 V644F, V644I,
646 11
564 11 L564L,
568 11 W568C, W568C,
652 11 Y652X,
557 11
649 11
565 11
623 11 T623I,
620 11 S620G, S620I,
620 11 S620G, S620I,
632 12 P632S, P632A,
640 12 F640Del, F640L, F640L, F640L, F640V,
626 12 G626V, G626A, G626S,
625 12 V625E,
648 12 G648A,
612 12 V612A, V612L, V612L,
631 12 S631F,
624 12 S624R, S624N, S624R, S624R,
622 12 L622F,
643 12
623 12 T623I,
628 13 G628Del, G628D, G628V, G628R, G628S, G628A,
560 13 I560M, I560fsX,
628 13 G628Del, G628D, G628V, G628R, G628S, G628A,
558 13 A558P, A558V, A558E,
649 13
617 13 F617L, F617L, F617V, F617L,
639 13 I639N, I639F,
647 13
616 13 Y616S,
627 13 F627L, F627L, F627fsX, F627X, F627L,
640 13 F640Del, F640L, F640L, F640L, F640V,
642 13 I642V, I642Del,
629 13 N629K, N629I, N629T, N629S, N629K, N629D,
643 13
585 14 W585C, W585C,
651 14 M651K,
647 14
611 14 Y611D,
630 14 V630I, V630A, V630T,
562 14 H562P, H562Q, H562Q, H562R,
637 14 E637X, E637K, E637G,
627 14 F627L, F627L, F627fsX, F627X, F627L,
633 14 N633S, N633I, N633D,
646 14
618 14 T618S, T618S,
621 14 S621R, S621R, S621R, S621N,
637 14 E637X, E637K, E637G,
652 15 Y652X,
656 15 F656L, F656L, F656L,
638 15 K638E, K638R, K638D, K638Del,
619 15
567 15 I567T, I567M,
566 15 C566F, C566S, C566R, C566S, C566G,