KCNQ1 Variant D202E Detail

We estimate the penetrance of LQTS for KCNQ1 D202E is 66%. We are unaware of any observations of this variant in individuals. D202E is not present in gnomAD. D202E 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D202E around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.67 1.0 -1 0.873 67
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 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.

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)
20421371 mouse ltk 11 54.6 1.0 0.333333333

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)
20421371 mouse ltk None None None

D202E 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
202 0 D202N, D202H,
201 5 I201del,
199 5 S199A,
240 5 H240R, H240P,
203 5 L203P,
198 6 I198V, I198T,
171 6
205 6 V205M,
200 7
204 7 I204M, I204F,
206 7 V206L,
167 8
174 8 R174H, R174C, R174L,
243 8 R243H, R243C, R243P, R243S,
168 9 G168R, G168R, G168R, G168R,
170 9
237 9
197 9 P197L,
236 9 L236Q, L236R,
239 9
194 9 A194P, A194T,
196 9
207 10 V207M, V207L, V207L, V207L, V207L, V207del,
193 11 F193L, F193L, F193L,
233 11 L233P,
175 11 L175I,
164 11
241 11 V241F, V241I, V241G,
172 11 V172M, V172E,
208 11 A208V,
115 11 E115A, E115G,
209 11 S209P,
242 11 D242N, D242Y,
169 12 T169M, T169R,
166 12 F166V,
114 12
244 12
173 12
238 12 M238V, M238L, M238L,
163 13
129 13 V129I,
133 13 V133I,
248 13 W248C, W248C, W248R, W248R,
165 13 V165M,
235 13 I235N,
245 13 G245V,
126 13 H126D,
234 13 Q234H, Q234H,
232 13
210 13 M210I, M210I, M210I,
195 14 R195Q, R195W,
130 14
177 14 S177F,
111 14 Y111C,
125 15
191 15
160 15 E160del, E160K, E160V,
178 15 A178T, A178del,
190 15 R190W, R190Q, R190L,
176 15
230 15