KCNH2 Variant K595N Detail

We estimate the penetrance of LQTS for KCNH2 K595N is 73%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. K595N is not present in gnomAD. K595N 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K595N around 73% (8/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.442 0.417 0 0.673 76
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 2 0 2
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
VARIANT FEATURES ALONE: - 10 4 6 -
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.

K595N has 30 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
595 0 K595N, K595N, K595E,
594 3
604 5 G604C, G604D, G604S,
605 5 P605L,
593 5 I593R, I593V, I593T, I593X, I593K,
596 5 P596T, P596L, P596S, P596R,
590 6 G590V, G590D,
606 7 S606Del, S606P, S606F,
589 8 L589P,
603 8 G603D,
597 8 Y597C, Y597H,
591 8 D591H, D591N,
592 9 Q592X,
609 10 D609N, D609G,
610 10
586 11 L586M,
583 11 I583V,
587 11
607 11
588 12 N588K, N588K, N588D,
635 12 N635I,
633 12 N633I, N633D, N633S,
634 12 T634P, T634I, T634S, T634A, T634S,
608 13
613 13 T613A, T613K, T613M, T613L,
585 14 W585C, W585C,
584 14 G584C, G584R, G584S,
577 14
612 14 V612L, V612A, V612L,
638 15 K638R, K638Del, K638D, K638E,