KCNH2 Variant G590D Detail

We estimate the penetrance of LQTS for KCNH2 G590D is 59%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. G590D is not present in gnomAD. G590D 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G590D around 59% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.631 0.559 -2 0.785 58
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
Japan Cohort 2020 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 5 5 -
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.

G590D has 41 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
590 0 G590D, G590V,
591 4 D591N, D591H,
589 4 L589P,
593 5 I593V, I593K, I593X, I593T, I593R,
596 5 P596L, P596R, P596T, P596S,
595 6 K595N, K595N, K595E,
592 6 Q592X,
594 6
588 6 N588D, N588K, N588K,
587 7
597 7 Y597H, Y597C,
605 7 P605L,
586 7 L586M,
604 8 G604S, G604D, G604C,
585 10 W585C, W585C,
584 10 G584R, G584C, G584S,
603 10 G603D,
610 10
606 11 S606P, S606F, S606Del,
633 11 N633I, N633D, N633S,
609 11 D609G, D609N,
613 12 T613L, T613M, T613A, T613K,
583 12 I583V,
583 12 I583V,
629 12 N629T, N629K, N629D, N629S, N629K, N629I,
630 12 V630A, V630I, V630T,
634 13 T634A, T634S, T634S, T634P, T634I,
631 13 S631F,
635 13 N635I,
572 13 G572C, G572S, G572D, G572R,
576 14
607 14
584 14 G584R, G584C, G584S,
638 14 K638R, K638Del, K638E, K638D,
569 14 Y569H, Y569C, Y569X,
633 14 N633I, N633D, N633S,
573 14
612 14 V612A, V612L, V612L,
628 14 G628R, G628Del, G628S, G628V, G628D, G628A,
614 14 A614T, A614V,
632 15 P632S, P632A,