KCNH2 Variant P605R Detail

We estimate the penetrance of LQTS for KCNH2 P605R is 82%. We are unaware of any observations of this variant in individuals. P605R is not present in gnomAD. P605R 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P605R around 82% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.503 0.996 -2 0.929 88
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 2 8 -
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.

P605R 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
605 0 P605L,
604 3 G604S, G604D, G604C,
606 4 S606P, S606F, S606Del,
595 5 K595N, K595N, K595E,
610 6
603 7 G603D,
609 7 D609G, D609N,
607 7
589 7 L589P,
590 7 G590D, G590V,
597 7 Y597H, Y597C,
586 8 L586M,
593 8 I593V, I593K, I593X, I593T, I593R,
596 8 P596L, P596R, P596T, P596S,
594 8
587 10
608 10
613 11 T613L, T613M, T613A, T613K,
569 11 Y569H, Y569C, Y569X,
591 11 D591N, D591H,
585 11 W585C, W585C,
592 11 Q592X,
635 11 N635I,
588 11 N588D, N588K, N588K,
573 12
612 12 V612A, V612L, V612L,
431 12 F431L, F431L, F431L,
572 12 G572C, G572S, G572D, G572R,
611 13 Y611D,
614 13 A614T, A614V,
634 13 T634A, T634S, T634S, T634P, T634I,
576 13
633 13 N633I, N633D, N633S,
584 13 G584R, G584C, G584S,
638 14 K638R, K638Del, K638E, K638D,
432 14
630 15 V630A, V630I, V630T,
568 15 W568C, W568C,
583 15 I583V,
570 15
430 15