KCNH2 Variant D591E Detail

We estimate the penetrance of LQTS for KCNH2 D591E is 20%. We are unaware of any observations of this variant in individuals. D591E is not present in gnomAD. D591E has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D591E around 20% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.269 0.0 2 0.606 31
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 9 1 -
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.

D591E has 35 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
591 0 D591N, D591H,
590 4 G590D, G590V,
592 5 Q592X,
588 5 N588D, N588K, N588K,
589 6 L589P,
596 7 P596L, P596R, P596T, P596S,
593 7 I593V, I593K, I593X, I593T, I593R,
594 7
587 8
595 8 K595N, K595N, K595E,
597 9 Y597H, Y597C,
586 10 L586M,
584 10 G584R, G584C, G584S,
605 11 P605L,
583 11 I583V,
633 11 N633I, N633D, N633S,
604 11 G604S, G604D, G604C,
585 11 W585C, W585C,
629 12 N629T, N629K, N629D, N629S, N629K, N629I,
583 12 I583V,
630 12 V630A, V630I, V630T,
631 13 S631F,
603 13 G603D,
633 13 N633I, N633D, N633S,
613 14 T613L, T613M, T613A, T613K,
628 14 G628R, G628Del, G628S, G628V, G628D, G628A,
584 14 G584R, G584C, G584S,
610 14
606 14 S606P, S606F, S606Del,
609 14 D609G, D609N,
592 14 Q592X,
588 14 N588D, N588K, N588K,
634 14 T634A, T634S, T634S, T634P, T634I,
631 15 S631F,
632 15 P632S, P632A,