KCNQ1 Variant R243P Detail

We estimate the penetrance of LQTS for KCNQ1 R243P is 73%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. R243P is not present in gnomAD. R243P 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R243P around 73% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.8 0.999 -3 0.957 78
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
16922724 2006 1 None 1 fetal, neonatal bradycardia
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
VARIANT FEATURES ALONE: - 10 3 7 -
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.

R243P 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
243 0 R243H, R243C, R243P, R243S,
242 5 D242N, D242Y,
244 5
115 6 E115A, E115G,
198 6 I198V, I198T,
241 6 V241F, V241I, V241G,
240 7 H240R, H240P,
245 7 G245V,
114 8
174 8 R174H, R174C, R174L,
126 8 H126D,
202 8 D202N, D202H,
117 9 P117L,
246 9
199 9 S199A,
239 9
196 9
248 9 W248C, W248C, W248R, W248R,
116 10
201 10 I201del,
247 10 T247I,
170 10
197 10 P197L,
111 10 Y111C,
129 11 V129I,
130 11
171 11
193 11 F193L, F193L, F193L,
113 11
125 11
112 12
249 12 R249S, R249S,
238 12 M238V, M238L, M238L,
167 12
122 12 C122Y,
200 12
267 12 Y267C,
123 13
194 13 A194P, A194T,
237 13
236 13 L236Q, L236R,
177 13 S177F,
118 13
175 13 L175I,
173 13
133 13 V133I,
110 13 V110I,
127 14 F127L, F127L, F127L,
203 14 L203P,
205 14 V205M,
178 14 A178T, A178del,
128 14 A128del,
119 14 G119R, G119V,
168 14 G168R, G168R, G168R, G168R,
181 14 R181C,
166 14 F166V,
184 14 Y184S, Y184C, Y184D, Y184H,
271 14
268 14 I268V, I268S,
264 15
204 15 I204M, I204F,
172 15 V172M, V172E,
124 15
206 15 V206L,