KCNH2 Variant N633D Detail

We estimate the penetrance of LQTS for KCNH2 N633D is 79%. This variant was found in a total of 1 carriers in 2 papers or gnomAD, 1 had LQTS. N633D is not present in gnomAD. N633D 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 N633D around 79% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.801 0.94 1 0.867 89
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
18593567 2008 1 0 1
16155735 2005 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
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)
18593567 HEK293 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)
18593567 HEK293 None None None

N633D has 64 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
633 0 N633I, N633D, N633S,
632 5 P632A, P632S,
634 5 T634S, T634I, T634S, T634A, T634P,
584 6 G584S, G584C, G584R,
631 6 S631F,
592 6 Q592X,
637 6 E637G, E637X, E637K,
629 6 N629D, N629I, N629K, N629K, N629S, N629T,
638 6 K638E, K638Del, K638R, K638D,
593 7 I593R, I593K, I593V, I593T, I593X,
583 7 I583V,
635 8 N635I,
588 9 N588K, N588D, N588K,
589 9 L589P,
585 9 W585C, W585C,
636 9
616 9 Y616S,
613 9 T613L, T613A, T613K, T613M,
630 9 V630A, V630T, V630I,
630 10 V630A, V630T, V630I,
628 10 G628D, G628A, G628S, G628V, G628Del, G628R,
627 10 F627fsX, F627L, F627L, F627L, F627X,
609 10 D609G, D609N,
594 11
590 11 G590D, G590V,
612 11 V612A, V612L, V612L,
587 11
568 11 W568C, W568C,
641 11 S641P, S641F,
588 11 N588K, N588D, N588K,
628 11 G628D, G628A, G628S, G628V, G628Del, G628R,
591 11 D591N, D591H,
586 11 L586M,
639 11 I639F, I639N,
572 12 G572D, G572R, G572C, G572S,
571 12 I571V, I571L,
595 12 K595E, K595N, K595N,
617 12 F617L, F617L, F617V, F617L,
575 12 E575K,
640 12 F640L, F640Del, F640L, F640L, F640V,
589 13 L589P,
629 13 N629D, N629I, N629K, N629K, N629S, N629T,
631 13 S631F,
614 13 A614T, A614V,
606 13 S606F, S606P, S606Del,
605 13 P605L,
642 13 I642V, I642Del,
585 13 W585C, W585C,
617 13 F617L, F617L, F617V, F617L,
591 13 D591N, D591H,
610 13
577 14
592 14 Q592X,
608 14
626 14 G626V, G626S, G626A,
586 14 L586M,
576 14
615 14 L615F, L615V,
620 14 S620I, S620G,
590 14 G590D, G590V,
626 15 G626V, G626S, G626A,
613 15 T613L, T613A, T613K, T613M,
621 15 S621R, S621R, S621R, S621N,
614 15 A614T, A614V,