KCNH2 Variant E50D Detail

We estimate the penetrance of LQTS for KCNH2 E50D is 65%. We are unaware of any observations of this variant in individuals. E50D is not present in gnomAD. E50D 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E50D around 65% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.366 0.0 0 0.621 73
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
29759541 2017 2 0 Short QT
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 4 6 -
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.

E50D has 36 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
50 0 E50X,
47 4 G47C, G47V,
49 5 C49G, C49R,
51 6
46 6 D46E, D46Y, D46E,
53 7 G53R, G53S,
52 7 C52W,
48 7
45 8 N45K, N45K, N45D,
28 9 K28E,
100 10 R100Q, R100P, R100G,
55 11 S55L,
27 11 R27P, R27X,
54 11 Y54X, Y54N,
44 11 C44F, C44X, C44W,
26 11 S26I,
56 12 R56Q,
101 12 K101E,
129 12 F129C,
29 12 F29S, F29V, F29L, F29L, F29L,
106 12 F106L, F106V, F106L, F106L,
102 13 D102H, D102X, D102V,
130 13 E130K,
131 13 V131L, V131fsX, V131L,
104 13
59 14
30 14 I30Del, I30T,
43 14 Y43C, Y43D,
23 14
108 14 C108Y,
128 14 N128S,
58 14 E58D, E58K, E58D,
741 14 K741R,
69 14 L69P, L69Del,
802 15
98 15