KCNH2 Variant D46E Detail

We estimate the penetrance of LQTS for KCNH2 D46E is 22%. This variant was found in a total of 6 carriers in 0 papers or gnomAD, 0 had LQTS. D46E is present in 6 alleles in gnomAD. D46E 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D46E around 22% (3/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.135 0.001 1 0.615 47
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: - 6 6 0 -
VARIANT FEATURES ALONE: - 10 7 3 -
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.

D46E 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
46 0 D46E, D46Y, D46E,
45 5 N45K, N45K, N45D,
47 5 G47V, G47C,
49 6 C49G, C49R,
50 6 E50X,
44 7 C44W, C44F, C44X,
56 8 R56Q,
48 8
43 9 Y43C, Y43D,
802 9
801 9 K801T,
29 10 F29L, F29L, F29L, F29V, F29S,
27 10 R27X, R27P,
28 10 K28E,
55 10 S55L,
800 10
23 10
26 10 S26I,
53 10 G53R, G53S,
51 11
803 11 D803Y, D803X,
52 11 C52W,
19 12 I19F,
30 12 I30T, I30Del,
59 12
799 13 L799sp,
741 13 K741R,
54 13 Y54X, Y54N,
798 13 I798fsX,
24 13
22 13 F22S, F22Y,
60 13 M60T,
129 13 F129C,
859 13 T859M, T859R,
57 13 A57P,
739 13 H739fsX,
740 14 C740W, C740G,
785 14 G785fsX, G785D, G785S,
857 14 E857X,
31 14 I31S,
782 14 I782fsX, I782N,
25 14 Q25P,
58 14 E58D, E58K, E58D,
783 14 S783P,
128 14 N128S,
804 14
786 15
42 15 I42N,
20 15 R20G, R20L,
41 15 V41A,