KCNQ1 Variant R231C Detail

We estimate the penetrance of LQTS for KCNQ1 R231C is 57%. This variant was found in a total of 51 carriers in 13 papers or gnomAD, 30 had LQTS. R231C is present in 1 alleles in gnomAD. R231C has been functionally characterized in 2 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 R231C around 57% (34/61).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.69 1.0 -6 0.967 58
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
32893267 2020 16 None 16 None
30758498 2019 1 None 1 None
26715165 2016 1 None 1 None
23193492 2012 3 1 2 AF
22613981 2012 8 6 2 AF
20850564 2011 18 11 7 None
19843919 2009 1 None 1 None
19716085 2009 1 None 1 None
17192539 2006 1 None 1 None
16922724 2006 1 None 1 bradycardia
15176425 2004 3 None 1 None
14998624 2004 3 3 None None
12205790 2002 4 None 4 None
LITERATURE, COHORT, AND GNOMAD: - 51 21 30
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)
19843919 CHO 5 None None None
30571187 HEK 52 None None None

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)
19843919 CHO 51 -4.0 None 1.0
30571187 HEK None None None

R231C has 70 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
231 0 R231C, R231H, R231S,
230 6
229 6 G229D,
140 6 S140G, S140R, S140R, S140R,
228 6
227 6
234 7 Q234H, Q234H,
144 7 T144A,
299 7
226 7 A226V,
278 8 Y278H,
143 8 S143F, S143P, S143Y,
232 8
281 8 Y281C,
141 8 V141M,
233 8 L233P,
235 9 I235N,
225 9 S225L, S225del,
282 9 L282P,
137 9 L137F, L137P,
285 10
136 10
156 11
298 11 S298I, S298N,
142 11
279 11 F279I,
222 11
277 11 S277L, S277del, S277P, S277W,
160 11 E160del, E160K, E160V,
145 11
275 11 F275del,
236 11 L236Q, L236R,
237 11
212 11
224 11 T224M,
139 11
274 12 I274V,
223 12
300 12 A300T, A300S,
153 12 T153M,
138 12
303 12 L303P,
297 12 G297S, G297D, G297R,
302 12 A302V, A302E, A302T,
152 12
280 12 V280A, V280E,
209 12 S209P,
149 12
283 13 A283G, A283T,
213 13
146 13 E146K, E146G, E146Q,
208 13 A208V,
276 13 S276del,
205 13 V205M,
238 14 M238V, M238L, M238L,
133 14 V133I,
286 14
221 14
301 14
296 14 F296S, F296L, F296L, F296L,
159 14 M159del,
157 14 F157C,
135 14
284 14 E284K,
148 14
155 14
154 14
217 15
134 15 L134P,
216 15 G216R,