KCNH2 Variant R5S Detail

We estimate the penetrance of LQTS for KCNH2 R5S is 26%. We are unaware of any observations of this variant in individuals. R5S is not present in gnomAD. R5S has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R5S around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.274 0.118 -2 0.744 29
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 8 2 -
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.

R5S has 53 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
5 0
6 5 G6R,
403 6
695 6
698 7 E698K, E698X,
699 7 E699D, E699D,
4 7
3 7
402 7 H402R,
7 8
481 9
482 9 V482A,
476 9 V476I,
8 9
702 9
694 9 R694H, R694C,
401 10
404 10
691 11
474 11 T474I,
696 11 R696H, R696C,
697 11 L697X,
692 11
541 12 R541H, R541C,
480 12 E480V,
483 12 V483I,
475 12 Y475Del, Y475C,
693 13 L693X,
9 13 A9V, A9T,
405 13
703 13
765 13
701 13
544 13 E544fsX, E544A,
540 13 D540fsX,
477 13
700 13
478 13 A478D,
408 13
681 13 R681W,
677 14 M677T,
407 14
766 14
764 14
690 14
484 14
473 14 T473P,
400 14 I400N,
680 15
684 15
689 15
10 15
767 15 D767X,