KCNH2 Variant G6D Detail

We estimate the penetrance of LQTS for KCNH2 G6D is 29%. We are unaware of any observations of this variant in individuals. G6D is not present in gnomAD. G6D 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 G6D around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.91 0.998 -2 0.856 33
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.

G6D has 51 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
6 0 G6R,
481 4
5 5
7 5
482 6 V482A,
699 6 E699D, E699D,
8 6
4 7
476 7 V476I,
480 8 E480V,
695 8
403 9
402 9 H402R,
765 9
9 9 A9T, A9V,
702 9
698 9 E698X, E698K,
483 10 V483I,
477 10
478 10 A478D,
3 10
703 10
475 10 Y475C, Y475Del,
474 11 T474I,
764 11
766 11
827 11
479 11
696 11 R696C, R696H,
10 11
401 12
484 12
700 12
767 13 D767X,
697 13 L697X,
694 13 R694H, R694C,
692 13
701 13
706 13 S706F, S706C,
404 14
826 14 T826I, T826A,
691 14
704 14 A704T, A704V,
763 14
693 14 L693X,
825 14
824 14
473 15 T473P,
541 15 R541C, R541H,
13 15 T13N,
540 15 D540fsX,