KCNH2 Variant I593L Detail

We estimate the penetrance of LQTS for KCNH2 I593L is 39%. We are unaware of any observations of this variant in individuals. I593L is not present in gnomAD. I593L 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I593L around 39% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.547 0.003 3 0.549 55
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 7 3 -
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.

I593L has 46 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
593 0 I593R, I593V, I593T, I593X, I593K,
594 4
592 5 Q592X,
595 5 K595N, K595N, K595E,
590 5 G590V, G590D,
589 5 L589P,
633 7 N633I, N633D, N633S,
591 7 D591H, D591N,
583 8 I583V,
605 8 P605L,
634 8 T634P, T634I, T634S, T634A, T634S,
596 8 P596T, P596L, P596S, P596R,
609 9 D609N, D609G,
606 9 S606Del, S606P, S606F,
635 9 N635I,
588 9 N588K, N588K, N588D,
604 9 G604C, G604D, G604S,
584 9 G584C, G584R, G584S,
613 10 T613A, T613K, T613M, T613L,
586 10 L586M,
610 10
629 11 N629T, N629I, N629S, N629D, N629K, N629K,
638 11 K638R, K638Del, K638D, K638E,
632 11 P632A, P632S,
597 11 Y597C, Y597H,
637 11 E637K, E637G, E637X,
587 12
612 12 V612L, V612A, V612L,
585 12 W585C, W585C,
630 12 V630A, V630I, V630T,
608 12
631 12 S631F,
636 12
603 13 G603D,
607 13
588 13 N588K, N588K, N588D,
577 13
616 13 Y616S,
587 13
614 14 A614V, A614T,
628 14 G628R, G628D, G628V, G628A, G628S, G628Del,
584 14 G584C, G584R, G584S,
575 14 E575K,
631 15 S631F,
585 15 W585C, W585C,
639 15 I639N, I639F,