KCNQ1 Variant C136S Detail

We estimate the penetrance of LQTS for KCNQ1 C136S is 43%. We are unaware of any observations of this variant in individuals. C136S is not present in gnomAD. C136S 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 C136S around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.98 0.796 4 0.789 45
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.

C136S has 63 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
136 0
137 4 L137F, L137P,
135 5
139 5
133 5 V133I,
234 5 Q234H, Q234H,
140 6 S140G, S140R, S140R, S140R,
138 6
159 6 M159del,
132 7 I132L,
134 7 L134P,
156 7
160 7 E160del, E160K, E160V,
237 7
163 8
141 9 V141M,
230 9
235 10 I235N,
142 10
238 10 M238V, M238L, M238L,
155 10
131 10
143 10 S143F, S143P, S143Y,
130 10
231 10 R231C, R231H, R231S,
233 10 L233P,
152 10
129 11 V129I,
162 11 V162M,
167 11
164 12
236 12 L236Q, L236R,
158 12
161 12
144 12 T144A,
154 12
128 12 A128del,
153 12 T153M,
299 12
229 12 G229D,
209 13 S209P,
157 13 F157C,
232 13
240 13 H240R, H240P,
205 13 V205M,
274 13 I274V,
166 13 F166V,
226 13 A226V,
239 14
213 14
148 14
149 14
145 14
241 14 V241F, V241I, V241G,
151 14
275 14 F275del,
227 15
165 15 V165M,
127 15 F127L, F127L, F127L,
278 15 Y278H,
206 15 V206L,
303 15 L303P,
212 15