KCNH2 Variant G719D Detail

We estimate the penetrance of LQTS for KCNH2 G719D is 41%. We are unaware of any observations of this variant in individuals. G719D is not present in gnomAD. G719D 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G719D around 41% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.717 0.63 -1 0.842 48
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 6 4 -
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.

G719D has 55 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
719 0
720 4
718 6
721 6 P721L,
717 6 L717P,
716 6 V716G,
715 8 A715sp, A715V, A715T, A715A,
725 8 Q725fsX, Q725R,
700 8
701 9
724 9 L724X,
704 9 A704T, A704V,
676 10 Q676X, Q676fsX,
697 10 L697X,
722 10
714 11
712 11 D712N,
680 11
723 11 C723X, C723G, C723R,
679 11 R679Q, R679W,
728 11
708 12
683 12
714 12
710 12
713 12 M713V,
703 12
713 13 M713V,
726 13
705 13 W705fsX, W705X,
711 13 I711V,
761 13
712 13 D712N,
756 13 M756V,
677 13 M677T,
702 13
707 13
696 14 R696H, R696C,
762 14
729 14
727 14
760 14
699 14 E699D, E699D,
698 14 E698X, E698K,
759 14 K759N, K759N,
715 14 A715sp, A715V, A715T, A715A,
706 14 S706C, S706F,
693 14 L693X,
673 14
672 15 R672C, R672H,
767 15 D767X,
764 15
763 15
675 15
684 15