KCNH2 Variant S786Y Detail

We estimate the penetrance of LQTS for KCNH2 S786Y is 49%. We are unaware of any observations of this variant in individuals. S786Y is not present in gnomAD. S786Y 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 S786Y around 49% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.786 0.998 -2 0.852 53
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.

S786Y has 68 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
786 0
785 4 G785fsX, G785S, G785D,
787 4
825 5
826 5 T826A, T826I,
800 6
828 6
824 6
16 6 D16A,
788 7 E788D, E788K, E788D,
799 7 L799sp,
798 7 I798fsX,
801 8 K801T,
782 8 I782N, I782fsX,
15 9 L15V,
19 9 I19F,
13 9 T13N,
797 9 A797T,
763 10
829 10 D829E, D829E, D829A,
784 10 R784G, R784Q, R784W,
803 10 D803Y, D803X,
765 10
783 10 S783P,
43 10 Y43C, Y43D,
827 10
20 10 R20G, R20L,
12 10 N12D,
830 11
789 11
764 11
17 11
822 11 V822M, V822L, V822L,
823 11 R823Q, R823T, R823W, R823fsX,
10 11
766 11
802 12
767 12 D767X,
42 12 I42N,
14 12
805 12 F805C, F805S,
18 12 I18M,
795 12 V795I,
769 13
44 13 C44X, C44F, C44W,
762 13
790 13
56 13 R56Q,
9 13 A9T, A9V,
796 13 V796Del, V796L, V796L,
31 13 I31S,
859 13 T859R, T859M,
479 14
804 14
23 14
45 14 N45D, N45K, N45K,
11 14 Q11H, Q11H, Q11L,
780 14
761 14
768 14
860 14
831 14
781 14
29 15 F29V, F29L, F29S, F29L, F29L,
46 15 D46Y, D46E, D46E,
60 15 M60T,
480 15 E480V,
821 15 D821E, D821E,