KCNQ1 Variant R237K Detail

We estimate the penetrance of LQTS for KCNQ1 R237K is 43%. We are unaware of any observations of this variant in individuals. R237K is not present in gnomAD. R237K 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 R237K around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.92 0.994 0 0.925 47
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.

R237K has 71 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
237 0
234 5 Q234H, Q234H,
233 5 L233P,
236 6 L236Q, L236R,
205 6 V205M,
133 6 V133I,
240 6 H240R, H240P,
235 7 I235N,
167 7
136 7
238 8 M238V, M238L, M238L,
163 8
160 8 E160del, E160K, E160V,
239 8
137 8 L137F, L137P,
230 8
209 8 S209P,
164 8
206 9 V206L,
202 9 D202N, D202H,
232 9
132 9 I132L,
201 10 I201del,
130 10
129 10 V129I,
208 10 A208V,
134 10 L134P,
229 10 G229D,
204 10 I204M, I204F,
241 10 V241F, V241I, V241G,
159 11 M159del,
166 11 F166V,
140 11 S140G, S140R, S140R, S140R,
135 11
231 11 R231C, R231H, R231S,
168 12 G168R, G168R, G168R, G168R,
203 12 L203P,
275 12 F275del,
207 12 V207M, V207L, V207L, V207L, V207L, V207del,
156 12
162 12 V162M,
170 12
161 12
165 12 V165M,
198 12 I198V, I198T,
213 12
212 12
274 13 I274V,
271 13
131 13
139 13
243 13 R243H, R243C, R243P, R243S,
138 13
226 13 A226V,
171 13
210 13 M210I, M210I, M210I,
199 13 S199A,
278 13 Y278H,
128 13 A128del,
242 13 D242N, D242Y,
126 14 H126D,
200 14
211 14
169 14 T169M, T169R,
225 14 S225L, S225del,
141 14 V141M,
267 14 Y267C,
174 15 R174H, R174C, R174L,
125 15
157 15 F157C,
299 15