KCNQ1 Variant S140R Detail

We estimate the penetrance of LQTS for KCNQ1 S140R is 52%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. S140R is not present in gnomAD. S140R has been functionally characterized in 1 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 S140R around 52% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.53 1.0 -3 0.729 49
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
26496715 2016 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
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)
30571187 HEK 10 None None 0.797571137

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)
30571187 HEK 40 6.0 None 0.880526416

S140R has 64 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
140 0 S140G, S140R, S140R, S140R,
141 4 V141M,
143 5 S143F, S143P, S143Y,
137 6 L137F, L137P,
231 6 R231C, R231H, R231S,
139 6
142 6
136 6
144 6 T144A,
234 6 Q234H, Q234H,
138 6
299 7
156 8
230 8
145 9
152 9
135 9
235 9 I235N,
160 10 E160del, E160K, E160V,
149 10
148 10
300 10 A300T, A300S,
153 10 T153M,
133 10 V133I,
229 10 G229D,
134 11 L134P,
159 11 M159del,
298 11 S298I, S298N,
227 11
155 11
233 11 L233P,
281 11 Y281C,
237 11
303 11 L303P,
226 11 A226V,
278 11 Y278H,
232 11
274 12 I274V,
228 12
146 12 E146K, E146G, E146Q,
154 12
238 12 M238V, M238L, M238L,
277 13 S277L, S277del, S277P, S277W,
302 13 A302V, A302E, A302T,
132 13 I132L,
147 13 Q147R,
297 13 G297S, G297D, G297R,
151 13
236 13 L236Q, L236R,
275 13 F275del,
157 13 F157C,
150 13 A150T,
301 13
163 14
225 14 S225L, S225del,
285 14
282 14 L282P,
222 14
209 14 S209P,
213 15
212 15
130 15
131 15
279 15 F279I,