KCNQ1 Variant I230N Detail

We estimate the penetrance of LQTS for KCNQ1 I230N is 46%. We are unaware of any observations of this variant in individuals. I230N is not present in gnomAD. I230N 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I230N around 46% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.32 0.999 -5 0.951 51
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 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.

I230N has 74 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
230 0
229 4 G229D,
226 5 A226V,
233 5 L233P,
234 6 Q234H, Q234H,
231 6 R231C, R231H, R231S,
212 7
209 7 S209P,
225 7 S225L, S225del,
160 7 E160del, E160K, E160V,
227 7
232 7
213 8
228 8
208 8 A208V,
237 8
140 8 S140G, S140R, S140R, S140R,
222 9
156 9
205 9 V205M,
235 9 I235N,
136 9
236 10 L236Q, L236R,
211 10
157 10 F157C,
137 10 L137F, L137P,
143 11 S143F, S143P, S143Y,
221 11
164 11
224 11 T224M,
216 11 G216R,
161 11
223 11
278 11 Y278H,
159 11 M159del,
206 11 V206L,
153 11 T153M,
163 12
210 12 M210I, M210I, M210I,
144 12 T144A,
215 12 V215M, V215G, V215L, V215L,
217 12
207 12 V207M, V207L, V207L, V207L, V207L, V207del,
214 12 C214Y,
141 12 V141M,
139 12
133 12 V133I,
152 12
204 12 I204M, I204F,
299 13
282 13 L282P,
154 13
155 13
275 13 F275del,
219 13 G219E,
167 13
281 13 Y281C,
162 14 V162M,
238 14 M238V, M238L, M238L,
138 14
142 14
135 14
149 14
279 14 F279I,
240 14 H240R, H240P,
158 14
274 15 I274V,
239 15
201 15 I201del,
165 15 V165M,
285 15
132 15 I132L,
134 15 L134P,
202 15 D202N, D202H,