KCNQ1 Variant E160D Detail

We estimate the penetrance of LQTS for KCNQ1 E160D is 83%. We are unaware of any observations of this variant in individuals. E160D is not present in gnomAD. E160D has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E160D around 83% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.77 0.998 6 0.796 91
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 LQT1 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 2 8 -
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.

E160D has 66 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. This results from the fact that the functional KV7.1 channel 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
160 0 E160del, E160K, E160V,
159 5 M159del,
161 5
156 6
163 6
164 6
213 7
157 7 F157C,
230 7
162 7 V162M,
136 7
209 7 S209P,
234 7 Q234H, Q234H,
158 8
237 8
233 9 L233P,
155 9
212 9
154 10
167 10
165 10 V165M,
226 10 A226V,
140 10 S140G, S140R, S140R, S140R,
139 10
133 10 V133I,
153 10 T153M,
205 10 V205M,
206 10 V206L,
132 11 I132L,
152 11
208 11 A208V,
229 11 G229D,
137 11 L137F, L137P,
210 11 M210I, M210I, M210I,
166 11 F166V,
216 11 G216R,
231 11 R231C, R231H, R231S,
135 11
214 12 C214Y,
211 12
222 12
217 12
143 12 S143F, S143P, S143Y,
227 13
235 13 I235N,
225 13 S225L, S225del,
168 13 G168R, G168R, G168R, G168R,
207 13 V207M, V207L, V207L, V207L, V207L, V207del,
236 13 L236Q, L236R,
232 13
138 13
215 13 V215M, V215G, V215L, V215L,
129 13 V129I,
134 14 L134P,
240 14 H240R, H240P,
141 14 V141M,
142 14
149 14
238 14 M238V, M238L, M238L,
169 15 T169M, T169R,
221 15
228 15
202 15 D202N, D202H,
144 15 T144A,
151 15
204 15 I204M, I204F,