KCNQ1 Variant I235N Detail

We estimate the penetrance of LQTS for KCNQ1 I235N is 29%. This variant was found in a total of 19 carriers in 8 papers or gnomAD, 4 had LQTS. I235N is not present in gnomAD. I235N 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I235N around 29% (8/29).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.8 0.985 -4 0.948 42
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
32893267 2020 1 None 1 None
31520628 2019 1 None 1 1 miscarriage
24269949 2014 15 15 None None
22949429 2012 2 None 2 None
21956039 2011 2 None 2 None
19841300 2009 2 None 2 None
19716085 2009 2 None 2 None
19590188 2009 None None None None
LITERATURE, COHORT, AND GNOMAD: - 19 15 4
VARIANT FEATURES ALONE: - 10 6 4 -
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)
24269949 HEK 10 None None None
19590188 Oocytes None None None

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)
24269949 HEK 70 16.0 None None
19590188 Oocytes 25 None None None

I235N 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
235 0 I235N,
236 5 L236Q, L236R,
275 5 F275del,
232 5
234 5 Q234H, Q234H,
238 6 M238V, M238L, M238L,
274 6 I274V,
233 7 L233P,
137 7 L137F, L137P,
237 7
278 7 Y278H,
239 7
271 8
231 9 R231C, R231H, R231S,
133 9 V133I,
229 9 G229D,
230 9
140 9 S140G, S140R, S140R, S140R,
272 9 G272D, G272S, G272V,
136 10
299 10
277 10 S277L, S277del, S277P, S277W,
240 10 H240R, H240P,
279 10 F279I,
205 10 V205M,
134 10 L134P,
276 10 S276del,
273 10 L273F, L273V, L273R,
141 11 V141M,
303 11 L303P,
201 11 I201del,
130 11
267 12 Y267C,
138 12
241 12 V241F, V241I, V241G,
270 12 F270S,
282 12 L282P,
228 12
204 13 I204M, I204F,
269 13 G269D, G269S, G269del,
209 13 S209P,
160 13 E160del, E160K, E160V,
135 13
281 13 Y281C,
268 13 I268V, I268S,
202 13 D202N, D202H,
208 13 A208V,
302 13 A302V, A302E, A302T,
280 13 V280A, V280E,
332 13
139 13
226 13 A226V,
144 14 T144A,
132 14 I132L,
248 14 W248C, W248C, W248R, W248R,
242 14 D242N, D242Y,
167 14
225 14 S225L, S225del,
300 14 A300T, A300S,
143 14 S143F, S143P, S143Y,
227 14
206 14 V206L,
163 14
198 14 I198V, I198T,
156 14
129 14 V129I,
306 15 G306V, G306R, G306R,
131 15
164 15
142 15
212 15
159 15 M159del,