KCNQ1 Variant E115G Detail

We estimate the penetrance of LQTS for KCNQ1 E115G is 83%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. E115G is not present in gnomAD. E115G has been functionally characterized in 1 papers. 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 E115G around 83% (9/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.39 0.982 -2 0.937 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
32893267 2020 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
30571187 HEK -7 None None 0.0

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
30571187 HEK 51 7.1 None 1.152143913

E115G has 61 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
115 0 E115A, E115G,
114 5
111 5 Y111C,
243 6 R243H, R243C, R243P, R243S,
174 6 R174H, R174C, R174L,
244 6
116 6
112 7
117 7 P117L,
113 8
177 8 S177F,
193 9 F193L, F193L, F193L,
110 9 V110I,
178 9 A178T, A178del,
198 9 I198V, I198T,
126 9 H126D,
181 9 R181C,
196 10
170 10
199 10 S199A,
108 10 G108S,
122 10 C122Y,
173 10
242 10 D242N, D242Y,
245 10 G245V,
180 10
175 11 L175I,
184 11 Y184S, Y184C, Y184D, Y184H,
241 11 V241F, V241I, V241G,
171 11
118 11
202 11 D202N, D202H,
240 11 H240R, H240P,
125 11
246 12
107 12 Q107H, Q107H,
179 12 G179S,
119 12 G119R, G119V,
194 12 A194P, A194T,
197 13 P197L,
183 13 K183R,
172 13 V172M, V172E,
176 13
190 13 R190W, R190Q, R190L,
109 13 R109C, R109L,
129 13 V129I,
123 14
201 14 I201del,
167 14
249 14 R249S, R249S,
248 14 W248C, W248C, W248R, W248R,
200 14
247 14 T247I,
168 14 G168R, G168R, G168R, G168R,
121 14
239 14
189 14 G189R, G189R, G189E,
169 14 T169M, T169R,
106 14
182 15
166 15 F166V,