KCNQ1 Variant L236R Detail

We estimate the penetrance of LQTS for KCNQ1 L236R is 75%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 1 had LQTS. L236R is not present in gnomAD. L236R has been functionally characterized in 2 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L236R around 75% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.83 1.0 1 0.963 78
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: - 1 0 1
VARIANT FEATURES ALONE: - 10 3 7 -
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)
26066609 Oocytes 0 54.0 None None
30571187 HEK 1 None None 0.566198799

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)
26066609 Oocytes 30 0.0 0.95 0.6
30571187 HEK None None None

L236R has 62 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
236 0 L236Q, L236R,
235 5 I235N,
233 5 L233P,
232 5
239 5
237 6
205 6 V205M,
201 7 I201del,
240 7 H240R, H240P,
234 7 Q234H, Q234H,
238 7 M238V, M238L, M238L,
275 7 F275del,
204 8 I204M, I204F,
202 9 D202N, D202H,
229 9 G229D,
271 9
278 10 Y278H,
230 10
274 10 I274V,
133 10 V133I,
208 10 A208V,
137 10 L137F, L137P,
198 10 I198V, I198T,
209 11 S209P,
206 11 V206L,
241 11 V241F, V241I, V241G,
231 11 R231C, R231H, R231S,
200 11
203 12 L203P,
272 12 G272D, G272S, G272V,
167 12
279 12 F279I,
136 12
248 12 W248C, W248C, W248R, W248R,
242 12 D242N, D242Y,
199 12 S199A,
130 12
207 12 V207M, V207L, V207L, V207L, V207L, V207del,
197 12 P197L,
267 13 Y267C,
160 13 E160del, E160K, E160V,
134 13 L134P,
164 13
243 13 R243H, R243C, R243P, R243S,
140 13 S140G, S140R, S140R, S140R,
276 13 S276del,
268 13 I268V, I268S,
277 14 S277L, S277del, S277P, S277W,
163 14
228 14
225 14 S225L, S225del,
212 14
226 14 A226V,
273 14 L273F, L273V, L273R,
299 14
129 14 V129I,
282 14 L282P,
132 14 I132L,
269 15 G269D, G269S, G269del,
171 15
332 15
245 15 G245V,