KCNQ1 Variant G168E Detail

We estimate the penetrance of LQTS for KCNQ1 G168E is 38%. We are unaware of any observations of this variant in individuals. G168E is not present in gnomAD. G168E 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G168E around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.28 0.999 -3 0.96 43
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 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.

G168E has 49 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
168 0 G168R, G168R, G168R, G168R,
169 4 T169M, T169R,
171 6
167 6
170 6
165 6 V165M,
172 6 V172M, V172E,
166 6 F166V,
206 6 V206L,
164 7
173 8
203 9 L203P,
202 9 D202N, D202H,
174 9 R174H, R174C, R174L,
163 9
175 10 L175I,
205 10 V205M,
207 10 V207M, V207L, V207L, V207L, V207L, V207del,
162 10 V162M,
210 11 M210I, M210I, M210I,
176 11
209 11 S209P,
199 11 S199A,
240 11 H240R, H240P,
161 12
237 12
114 12
204 12 I204M, I204F,
208 12 A208V,
160 13 E160del, E160K, E160V,
129 13 V129I,
201 13 I201del,
125 13
194 13 A194P, A194T,
177 14 S177F,
200 14
198 14 I198V, I198T,
193 14 F193L, F193L, F193L,
233 14 L233P,
213 14
243 14 R243H, R243C, R243P, R243S,
115 14 E115A, E115G,
126 14 H126D,
110 15 V110I,
211 15
132 15 I132L,
159 15 M159del,
190 15 R190W, R190Q, R190L,
133 15 V133I,