KCNQ1 Variant S209P Detail

We estimate the penetrance of LQTS for KCNQ1 S209P is 13%. This variant was found in a total of 6 carriers in 1 papers or gnomAD, 0 had LQTS. S209P is not present in gnomAD. S209P has been functionally characterized in 2 papers. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S209P around 13% (2/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.66 1.0 -4 0.925 22
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
19632626 2009 6 6 None 5 AF
LITERATURE, COHORT, AND GNOMAD: - 6 6 0
VARIANT FEATURES ALONE: - 10 8 2 -
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)
19632626 COS 200 -42.4 None 5.7
30571187 HEK 86 -0.9 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)
19632626 COS 110 None None None
30571187 HEK None None None

S209P has 58 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
209 0 S209P,
208 4 A208V,
212 5
210 5 M210I, M210I, M210I,
206 5 V206L,
213 6
205 6 V205M,
207 6 V207M, V207L, V207L, V207L, V207L, V207del,
211 6
164 6
233 6 L233P,
230 7
160 7 E160del, E160K, E160V,
229 8 G229D,
237 8
161 8
214 8 C214Y,
226 9 A226V,
204 9 I204M, I204F,
234 9 Q234H, Q234H,
225 10 S225L, S225del,
163 10
203 10 L203P,
167 10
165 10 V165M,
215 10 V215M, V215G, V215L, V215L,
216 11 G216R,
232 11
236 11 L236Q, L236R,
168 11 G168R, G168R, G168R, G168R,
221 11
157 11 F157C,
202 11 D202N, D202H,
162 11 V162M,
222 11
159 12 M159del,
156 12
201 12 I201del,
231 12 R231C, R231H, R231S,
136 13
227 13
235 13 I235N,
240 13 H240R, H240P,
166 13 F166V,
228 13
171 13
217 13
224 14 T224M,
133 14 V133I,
169 14 T169M, T169R,
158 14
219 14 G219E,
140 14 S140G, S140R, S140R, S140R,
223 14
200 14
137 15 L137F, L137P,
170 15
239 15