KCNH2 Variant T634N Detail

We estimate the penetrance of LQTS for KCNH2 T634N is 80%. We are unaware of any observations of this variant in individuals. T634N is not present in gnomAD. T634N 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T634N around 80% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.834 0.995 0 0.891 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.

T634N has 59 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
634 0 T634S, T634I, T634S, T634P, T634A,
637 4 E637G, E637X, E637K,
635 4 N635I,
633 5 N633D, N633I, N633S,
636 5
638 6 K638Del, K638E, K638D, K638R,
632 6 P632S, P632A,
584 6 G584C, G584S, G584R,
583 8 I583V,
593 8 I593X, I593V, I593R, I593K, I593T,
575 8 E575K,
571 8 I571V, I571L,
639 9 I639F, I639N,
609 9 D609N, D609G,
631 9 S631F,
585 9 W585C, W585C,
612 9 V612L, V612A, V612L,
572 9 G572S, G572R, G572C, G572D,
592 10 Q592X,
613 10 T613A, T613L, T613K, T613M,
568 10 W568C, W568C,
616 10 Y616S,
629 10 N629K, N629S, N629K, N629I, N629D, N629T,
640 10 F640L, F640V, F640L, F640L, F640Del,
641 10 S641F, S641P,
608 11
589 11 L589P,
577 11
594 11
586 11 L586M,
588 11 N588K, N588K, N588D,
587 11
606 12 S606P, S606F, S606Del,
576 12
595 12 K595N, K595E, K595N,
642 12 I642Del, I642V,
630 12 V630I, V630T, V630A,
570 12
627 13 F627X, F627L, F627fsX, F627L, F627L,
630 13 V630I, V630T, V630A,
573 13
590 13 G590D, G590V,
617 13 F617V, F617L, F617L, F617L,
610 13
605 13 P605L,
574 13 M574V, M574L, M574L,
614 13 A614T, A614V,
615 14 L615V, L615F,
628 14 G628V, G628R, G628A, G628D, G628Del, G628S,
611 14 Y611D,
567 14 I567M, I567T,
569 14 Y569H, Y569C, Y569X,
643 14
591 14 D591N, D591H,
607 14
588 15 N588K, N588K, N588D,
589 15 L589P,
644 15 V644F, V644I,
628 15 G628V, G628R, G628A, G628D, G628Del, G628S,