KCNH2 Variant I789F Detail

We estimate the penetrance of LQTS for KCNH2 I789F is 53%. We are unaware of any observations of this variant in individuals. I789F is not present in gnomAD. I789F 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I789F around 53% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.857 0.999 0 0.939 62
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 5 5 -
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.

I789F has 77 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
789 0
797 4 A797T,
790 5
796 5 V796L, V796Del, V796L,
788 5 E788D, E788K, E788D,
822 5 V822L, V822M, V822L,
820 7 G820R, G820R,
860 7
821 7 D821E, D821E,
795 7 V795I,
787 7
799 7 L799sp,
798 8 I798fsX,
823 8 R823Q, R823fsX, R823W, R823T,
791 8 R791W, R791Q,
819 8 N819K, N819K,
42 8 I42N,
794 9 V794D, V794I,
805 9 F805S, F805C,
862 9 L862P,
770 9
824 10
859 10 T859M, T859R,
61 10 Q61R,
60 10 M60T,
792 10
769 10
786 11
806 11 G806R, G806R,
818 11 S818A, S818L, S818W,
825 11
771 11 H771R, H771fsX,
12 11 N12D,
768 11
793 11 D793N,
772 11
800 11
861 11 N861I, N861H,
803 12 D803Y, D803X,
41 12 V41A,
40 12
780 12
33 12 N33T,
43 12 Y43C, Y43D,
15 12 L15V,
804 12
782 12 I782fsX, I782N,
766 13
56 13 R56Q,
31 13 I31S,
767 13 D767X,
858 13 I858T, I858V,
36 13 V36X,
776 13 L776I, L776P,
828 13
774 13 D774X, D774Y,
32 13 A32T,
44 14 C44X, C44F, C44W,
785 14 G785D, G785fsX, G785S,
57 14 A57P,
773 14
807 14 E807X,
11 14 Q11L, Q11H, Q11H,
863 14 R863X, R863P,
826 14 T826A, T826I,
10 14
763 14
830 14
13 14 T13N,
124 14 M124R, M124T,
35 15 R35W,
16 15 D16A,
778 15 A778T,
779 15
59 15
765 15
14 15