KCNH2 Variant H7D Detail

We estimate the penetrance of LQTS for KCNH2 H7D is 19%. We are unaware of any observations of this variant in individuals. H7D is not present in gnomAD. H7D 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H7D around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.929 0.243 -2 0.78 20
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 9 1 -
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.

H7D has 50 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
7 0
8 4
6 5 G6R,
9 6 A9T, A9V,
765 6
699 7 E699D, E699D,
766 7
481 7
695 7
10 7
5 8
482 8 V482A,
696 9 R696H, R696C,
764 9
767 9 D767X,
480 10 E480V,
692 11
824 11
827 11
825 11
11 11 Q11L, Q11H, Q11H,
698 11 E698X, E698K,
4 11
476 11 V476I,
403 11
703 12
13 12 T13N,
826 12 T826A, T826I,
823 12 R823Q, R823fsX, R823W, R823T,
700 12
483 12 V483I,
763 12
693 12 L693X,
697 12 L697X,
702 12
768 12
691 13
478 13 A478D,
479 13
402 13 H402R,
477 13
12 13 N12D,
694 13 R694C, R694H,
484 14
724 14 L724X,
828 14
474 14 T474I,
401 14
475 14 Y475Del, Y475C,
3 14