KCNH2 Variant N588T Detail

We estimate the penetrance of LQTS for KCNH2 N588T is 45%. We are unaware of any observations of this variant in individuals. N588T is not present in gnomAD. N588T 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N588T around 45% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.251 0.071 2 0.642 59
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 6 4 -
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.

N588T has 57 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
588 0 N588K, N588K, N588D,
589 5 L589P,
591 5 D591N, D591H,
592 6 Q592X,
584 6 G584S, G584C, G584R,
590 6 G590V, G590D,
587 6
585 7 W585C, W585C,
586 7 L586M,
631 8 S631F,
630 8 V630I, V630A, V630T,
583 8 I583V,
633 9 N633S, N633I, N633D,
629 9 N629K, N629I, N629T, N629S, N629K, N629D,
593 9 I593K, I593T, I593X, I593R, I593V,
628 10 G628Del, G628D, G628V, G628R, G628S, G628A,
632 10 P632S, P632A,
592 11 Q592X,
613 11 T613K, T613M, T613L, T613A,
629 11 N629K, N629I, N629T, N629S, N629K, N629D,
597 11 Y597C, Y597H,
596 11 P596S, P596T, P596R, P596L,
633 11 N633S, N633I, N633D,
637 11 E637X, E637K, E637G,
594 11
634 11 T634P, T634S, T634I, T634S, T634A,
605 11 P605L,
595 12 K595E, K595N, K595N,
572 12 G572S, G572C, G572R, G572D,
568 12 W568C, W568C,
610 12
617 13 F617L, F617L, F617V, F617L,
628 13 G628Del, G628D, G628V, G628R, G628S, G628A,
593 13 I593K, I593T, I593X, I593R, I593V,
614 13 A614T, A614V,
609 13 D609N, D609G,
604 13 G604C, G604S, G604D,
616 13 Y616S,
576 13
632 13 P632S, P632A,
631 13 S631F,
627 14 F627L, F627L, F627fsX, F627X, F627L,
638 14 K638E, K638R, K638D, K638Del,
569 14 Y569X, Y569C, Y569H,
571 14 I571L, I571V,
573 14
638 14 K638E, K638R, K638D, K638Del,
591 14 D591N, D591H,
606 14 S606F, S606Del, S606P,
627 14 F627L, F627L, F627fsX, F627X, F627L,
577 14
634 15 T634P, T634S, T634I, T634S, T634A,
612 15 V612A, V612L, V612L,
594 15
583 15 I583V,
628 15 G628Del, G628D, G628V, G628R, G628S, G628A,
636 15