KCNQ1 Variant L233R Detail

We estimate the penetrance of LQTS for KCNQ1 L233R is 30%. We are unaware of any observations of this variant in individuals. L233R is not present in gnomAD. L233R has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L233R around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.4 1.0 -4 0.938 33
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 8 2 -
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.

L233R has 72 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
233 0 L233P,
232 5
205 5 V205M,
230 5
236 5 L236Q, L236R,
229 5 G229D,
234 5 Q234H, Q234H,
237 5
209 6 S209P,
208 7 A208V,
235 7 I235N,
204 8 I204M, I204F,
231 8 R231C, R231H, R231S,
206 9 V206L,
212 9
160 9 E160del, E160K, E160V,
226 9 A226V,
225 9 S225L, S225del,
207 10 V207M, V207L, V207L, V207L, V207L, V207del,
201 10 I201del,
164 10
240 10 H240R, H240P,
136 10
278 10 Y278H,
239 10
228 10
137 10 L137F, L137P,
213 10
275 11 F275del,
202 11 D202N, D202H,
238 11 M238V, M238L, M238L,
211 11
133 11 V133I,
140 11 S140G, S140R, S140R, S140R,
167 11
210 11 M210I, M210I, M210I,
163 11
203 11 L203P,
227 11
156 12
161 13
274 13 I274V,
279 13 F279I,
159 13 M159del,
221 13
222 13
282 13 L282P,
224 14 T224M,
200 14
299 14
271 14
168 14 G168R, G168R, G168R, G168R,
134 14 L134P,
214 14 C214Y,
157 14 F157C,
198 14 I198V, I198T,
132 14 I132L,
141 14 V141M,
165 14 V165M,
162 14 V162M,
143 14 S143F, S143P, S143Y,
130 14
199 15 S199A,
139 15
216 15 G216R,
215 15 V215M, V215G, V215L, V215L,
135 15
241 15 V241F, V241I, V241G,
223 15
166 15 F166V,
144 15 T144A,
171 15