KCNH2 Variant S631V Detail

We estimate the penetrance of LQTS for KCNH2 S631V is 84%. We are unaware of any observations of this variant in individuals. S631V is not present in gnomAD. S631V 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S631V around 84% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 91
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 2 8 -
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)
10354437 Xeno 50 -8.1 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)
10354437 Xeno None None None

S631V has 78 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
631 0 S631F,
632 4 P632S, P632A,
630 4 V630I, V630A, V630T,
629 5 N629K, N629I, N629T, N629S, N629K, N629D,
633 6 N633S, N633I, N633D,
628 6 G628Del, G628D, G628V, G628R, G628S, G628A,
627 6 F627L, F627L, F627fsX, F627X, F627L,
628 7 G628Del, G628D, G628V, G628R, G628S, G628A,
585 7 W585C, W585C,
617 7 F617L, F617L, F617V, F617L,
637 7 E637X, E637K, E637G,
629 7 N629K, N629I, N629T, N629S, N629K, N629D,
588 8 N588K, N588K, N588D,
584 8 G584S, G584C, G584R,
638 8 K638E, K638R, K638D, K638Del,
568 9 W568C, W568C,
616 9 Y616S,
634 9 T634P, T634S, T634I, T634S, T634A,
626 9 G626V, G626A, G626S,
641 9 S641P, S641F,
592 10 Q592X,
630 10 V630I, V630A, V630T,
626 10 G626V, G626A, G626S,
627 10 F627L, F627L, F627fsX, F627X, F627L,
589 10 L589P,
616 10 Y616S,
613 10 T613K, T613M, T613L, T613A,
621 11 S621R, S621R, S621R, S621N,
620 11 S620G, S620I,
592 11 Q592X,
586 11 L586M,
614 11 A614T, A614V,
640 11 F640Del, F640L, F640L, F640L, F640V,
583 11 I583V,
625 12 V625E,
636 12
618 12 T618S, T618S,
613 12 T613K, T613M, T613L, T613A,
628 12 G628Del, G628D, G628V, G628R, G628S, G628A,
620 12 S620G, S620I,
635 12 N635I,
587 12
593 12 I593K, I593T, I593X, I593R, I593V,
571 12 I571L, I571V,
631 12 S631F,
631 12 S631F,
625 13 V625E,
632 13 P632S, P632A,
628 13 G628Del, G628D, G628V, G628R, G628S, G628A,
645 13 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
572 13 G572S, G572C, G572R, G572D,
591 13 D591N, D591H,
589 13 L589P,
633 13 N633S, N633I, N633D,
642 13 I642V, I642Del,
639 13 I639N, I639F,
644 13 V644F, V644I,
626 13 G626V, G626A, G626S,
617 13 F617L, F617L, F617V, F617L,
590 13 G590V, G590D,
627 13 F627L, F627L, F627fsX, F627X, F627L,
588 13 N588K, N588K, N588D,
638 13 K638E, K638R, K638D, K638Del,
626 14 G626V, G626A, G626S,
612 14 V612A, V612L, V612L,
565 14
615 14 L615F, L615V,
629 14 N629K, N629I, N629T, N629S, N629K, N629D,
624 14 S624R, S624N, S624R, S624R,
593 15 I593K, I593T, I593X, I593R, I593V,
569 15 Y569X, Y569C, Y569H,
612 15 V612A, V612L, V612L,
610 15
564 15 L564L,
614 15 A614T, A614V,
622 15 L622F,
591 15 D591N, D591H,
619 15