KCNQ1 Variant L239R Detail

We estimate the penetrance of LQTS for KCNQ1 L239R is 51%. We are unaware of any observations of this variant in individuals. L239R is not present in gnomAD. L239R 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L239R around 51% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.59 0.999 1 0.957 56
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 5 5 -
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.

L239R has 63 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
239 0
240 5 H240R, H240P,
238 5 M238V, M238L, M238L,
236 5 L236Q, L236R,
241 7 V241F, V241I, V241G,
242 7 D242N, D242Y,
271 7
201 7 I201del,
248 7 W248C, W248C, W248R, W248R,
235 7 I235N,
198 8 I198V, I198T,
267 8 Y267C,
237 8
275 9 F275del,
243 9 R243H, R243C, R243P, R243S,
202 9 D202N, D202H,
268 9 I268V, I268S,
130 10
205 10 V205M,
133 10 V133I,
245 10 G245V,
274 10 I274V,
232 10
247 10 T247I,
233 10 L233P,
272 10 G272D, G272S, G272V,
234 11 Q234H, Q234H,
197 11 P197L,
199 11 S199A,
204 11 I204M, I204F,
137 12 L137F, L137P,
200 12
269 12 G269D, G269S, G269del,
246 12
134 12 L134P,
167 12
129 12 V129I,
270 12 F270S,
244 13
196 13
278 13 Y278H,
273 13 L273F, L273V, L273R,
126 13 H126D,
264 13
203 13 L203P,
206 14 V206L,
136 14
132 14 I132L,
249 14 R249S, R249S,
276 14 S276del,
115 14 E115A, E115G,
229 14 G229D,
251 14 L251P, L251Q,
279 15 F279I,
131 15
171 15
174 15 R174H, R174C, R174L,
266 15 L266P,
230 15
265 15 T265I,
170 15
209 15 S209P,
208 15 A208V,