KCNQ1 Variant Q234H Detail

We estimate the penetrance of LQTS for KCNQ1 Q234H is 25%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. Q234H is present in 1 alleles in gnomAD. Q234H 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 Q234H around 25% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.81 0.981 -3 0.929 29
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 1 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.

Q234H has 76 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
234 0 Q234H, Q234H,
237 5
233 5 L233P,
136 5
137 5 L137F, L137P,
235 5 I235N,
230 6
140 6 S140G, S140R, S140R, S140R,
231 7 R231C, R231H, R231S,
133 7 V133I,
236 7 L236Q, L236R,
232 7
160 7 E160del, E160K, E160V,
229 8 G229D,
238 8 M238V, M238L, M238L,
205 9 V205M,
156 9
209 9 S209P,
139 10
134 10 L134P,
135 10
138 10
141 10 V141M,
159 10 M159del,
163 10
226 10 A226V,
278 10 Y278H,
275 10 F275del,
299 11
274 11 I274V,
132 11 I132L,
240 11 H240R, H240P,
239 11
143 11 S143F, S143P, S143Y,
164 11
208 11 A208V,
167 11
130 12
212 12
227 12
228 12
144 12 T144A,
213 12
225 12 S225L, S225del,
206 12 V206L,
142 12
161 13
271 13
152 13
129 13 V129I,
204 13 I204M, I204F,
201 13 I201del,
157 13 F157C,
155 13
202 13 D202N, D202H,
162 13 V162M,
277 13 S277L, S277del, S277P, S277W,
153 14 T153M,
131 14
303 14 L303P,
281 14 Y281C,
279 14 F279I,
241 14 V241F, V241I, V241G,
207 14 V207M, V207L, V207L, V207L, V207L, V207del,
282 14 L282P,
222 14
166 14 F166V,
154 14
211 14
272 15 G272D, G272S, G272V,
158 15
210 15 M210I, M210I, M210I,
300 15 A300T, A300S,
145 15
276 15 S276del,
273 15 L273F, L273V, L273R,