KCNH2 Variant G603V Detail

We estimate the penetrance of LQTS for KCNH2 G603V is 79%. We are unaware of any observations of this variant in individuals. G603V is not present in gnomAD. G603V 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G603V around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.136 0.823 -3 0.743 81
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 3 7 -
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.

G603V has 21 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
603 0 G603D,
604 3 G604C, G604D, G604S,
597 6 Y597C, Y597H,
605 7 P605L,
596 7 P596T, P596L, P596S, P596R,
595 8 K595N, K595N, K595E,
606 10 S606Del, S606P, S606F,
590 10 G590V, G590D,
594 11
587 11
610 11
586 11 L586M,
607 11
589 12 L589P,
593 13 I593R, I593V, I593T, I593X, I593K,
576 13
591 13 D591H, D591N,
573 13
609 13 D609N, D609G,
569 14 Y569C, Y569X, Y569H,
572 15 G572D, G572S, G572R, G572C,