KCNH2 Variant N629H Detail

We estimate the penetrance of LQTS for KCNH2 N629H is 83%. We are unaware of any observations of this variant in individuals. N629H is not present in gnomAD. N629H 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 N629H around 83% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.834 1.0 0 0.938 96
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)
22573844 HEK293 -16.0 None None 0.509259259

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)
22573844 HEK293 None None None

N629H has 77 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
629 0 N629T, N629K, N629D, N629S, N629K, N629I,
628 4 G628R, G628Del, G628S, G628V, G628D, G628A,
630 5 V630A, V630I, V630T,
631 5 S631F,
632 6 P632S, P632A,
633 6 N633I, N633D, N633S,
627 6 F627L, F627fsX, F627L, F627X, F627L,
592 7 Q592X,
616 7 Y616S,
631 7 S631F,
628 8 G628R, G628Del, G628S, G628V, G628D, G628A,
638 8 K638R, K638Del, K638E, K638D,
626 9 G626S, G626A, G626V,
613 9 T613L, T613M, T613A, T613K,
630 9 V630A, V630I, V630T,
588 9 N588D, N588K, N588K,
589 9 L589P,
617 9 F617V, F617L, F617L, F617L,
628 10 G628R, G628Del, G628S, G628V, G628D, G628A,
627 10 F627L, F627fsX, F627L, F627X, F627L,
634 10 T634A, T634S, T634S, T634P, T634I,
637 10 E637G, E637X, E637K,
620 10 S620G, S620I,
626 10 G626S, G626A, G626V,
629 10 N629T, N629K, N629D, N629S, N629K, N629I,
629 10 N629T, N629K, N629D, N629S, N629K, N629I,
593 11 I593V, I593K, I593X, I593T, I593R,
588 11 N588D, N588K, N588K,
585 11 W585C, W585C,
641 11 S641P, S641F,
584 11 G584R, G584C, G584S,
632 11 P632S, P632A,
625 11 V625E,
614 11 A614T, A614V,
591 12 D591N, D591H,
617 12 F617V, F617L, F617L, F617L,
628 12 G628R, G628Del, G628S, G628V, G628D, G628A,
626 12 G626S, G626A, G626V,
590 12 G590D, G590V,
612 12 V612A, V612L, V612L,
635 12 N635I,
627 12 F627L, F627fsX, F627L, F627X, F627L,
585 12 W585C, W585C,
633 13 N633I, N633D, N633S,
621 13 S621R, S621R, S621R, S621N,
583 13 I583V,
609 13 D609G, D609N,
586 13 L586M,
621 13 S621R, S621R, S621R, S621N,
568 13 W568C, W568C,
584 13 G584R, G584C, G584S,
642 13 I642V, I642Del,
626 13 G626S, G626A, G626V,
615 13 L615F, L615V,
618 13 T618S, T618S,
645 13 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
636 13
620 13 S620G, S620I,
625 13 V625E,
568 13 W568C, W568C,
639 14 I639F, I639N,
625 14 V625E,
592 14 Q592X,
640 14 F640L, F640L, F640V, F640Del, F640L,
619 14
637 14 E637G, E637X, E637K,
630 14 V630A, V630I, V630T,
610 14
631 14 S631F,
594 15
627 15 F627L, F627fsX, F627L, F627X, F627L,
616 15 Y616S,
589 15 L589P,
592 15 Q592X,
587 15
629 15 N629T, N629K, N629D, N629S, N629K, N629I,
624 15 S624R, S624R, S624N, S624R,