KCNQ1 Variant A226P Detail

We estimate the penetrance of LQTS for KCNQ1 A226P is 70%. We are unaware of any observations of this variant in individuals. A226P is not present in gnomAD. A226P 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 A226P around 70% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.74 1.0 -2 0.958 76
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 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.

A226P has 56 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
226 0 A226V,
225 4 S225L, S225del,
227 4
222 4
230 5
212 5
229 5 G229D,
223 6
228 6
221 7
224 7 T224M,
213 7
231 7 R231C, R231H, R231S,
216 8 G216R,
215 8 V215M, V215G, V215L, V215L,
209 9 S209P,
217 9
219 9 G219E,
211 9
233 9 L233P,
208 9 A208V,
160 10 E160del, E160K, E160V,
157 10 F157C,
234 10 Q234H, Q234H,
232 10
214 10 C214Y,
220 11 Q220K,
156 11
153 11 T153M,
140 11 S140G, S140R, S140R, S140R,
218 11
143 11 S143F, S143P, S143Y,
210 12 M210I, M210I, M210I,
161 12
144 12 T144A,
205 13 V205M,
282 13 L282P,
154 13
237 13
278 13 Y278H,
152 13
207 13 V207M, V207L, V207L, V207L, V207L, V207del,
164 13
136 13
235 13 I235N,
285 14
149 14
236 14 L236Q, L236R,
281 14 Y281C,
206 14 V206L,
159 14 M159del,
155 14
141 15 V141M,
137 15 L137F, L137P,
299 15
204 15 I204M, I204F,