KCNH2 Variant R4W Detail

We estimate the penetrance of LQTS for KCNH2 R4W is 28%. We are unaware of any observations of this variant in individuals. R4W is not present in gnomAD. R4W 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 R4W around 28% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.344 1.0 -4 0.751 26
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.

R4W has 54 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
4 0
702 5
476 6 V476I,
3 6
6 7 G6R,
5 7
481 8
699 8 E699D, E699D,
478 9 A478D,
698 9 E698X, E698K,
703 9
706 9 S706F, S706C,
402 9 H402R,
540 9 D540fsX,
477 9
482 10 V482A,
701 10
480 10 E480V,
705 11 W705fsX, W705X,
673 11
475 11 Y475C, Y475Del,
403 11
541 11 R541C, R541H,
704 11 A704T, A704V,
7 11
695 12
479 12
677 12 M677T,
474 12 T474I,
700 12
544 12 E544A, E544fsX,
483 12 V483I,
827 13
8 13
539 13
697 13 L697X,
538 13
765 13
764 13
543 13 S543fsX,
674 14 H674Y, H674fsX,
694 14 R694H, R694C,
681 14 R681W,
537 14 R537W,
401 14
707 14
709 14
670 14
696 15 R696C, R696H,
404 15
492 15 H492Y,
708 15
542 15
680 15