KCNQ1 Variant E170D Detail

We estimate the penetrance of LQTS for KCNQ1 E170D is 47%. We are unaware of any observations of this variant in individuals. E170D is not present in gnomAD. E170D 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E170D around 47% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.76 1.0 4 0.858 51
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 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.

E170D has 58 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
170 0
174 5 R174H, R174C, R174L,
169 5 T169M, T169R,
166 6 F166V,
168 6 G168R, G168R, G168R, G168R,
167 6
173 6
114 7
171 7
172 7 V172M, V172E,
125 8
202 9 D202N, D202H,
126 9 H126D,
129 9 V129I,
175 9 L175I,
113 9
165 10 V165M,
115 10 E115A, E115G,
240 10 H240R, H240P,
110 10 V110I,
243 10 R243H, R243C, R243P, R243S,
176 10
164 10
163 10
177 11 S177F,
206 11 V206L,
199 11 S199A,
203 11 L203P,
111 12 Y111C,
198 12 I198V, I198T,
237 12
241 12 V241F, V241I, V241G,
205 12 V205M,
128 12 A128del,
122 12 C122Y,
193 13 F193L, F193L, F193L,
162 13 V162M,
132 13 I132L,
178 13 A178T, A178del,
107 13 Q107H, Q107H,
117 13 P117L,
201 13 I201del,
133 13 V133I,
112 13
130 14
194 14 A194P, A194T,
244 14
121 14
124 14
200 14
108 15 G108S,
190 15 R190W, R190Q, R190L,
207 15 V207M, V207L, V207L, V207L, V207L, V207del,
204 15 I204M, I204F,
196 15
239 15
242 15 D242N, D242Y,
209 15 S209P,