KCNQ1 Variant L213P Detail

We estimate the penetrance of LQTS for KCNQ1 L213P is 46%. We are unaware of any observations of this variant in individuals. L213P is not present in gnomAD. L213P 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L213P around 46% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.36 0.981 -4 0.951 51
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 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.

L213P has 52 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
213 0
212 4
214 5 C214Y,
216 5 G216R,
209 6 S209P,
161 6
157 6 F157C,
211 7
210 7 M210I, M210I, M210I,
215 7 V215M, V215G, V215L, V215L,
160 7 E160del, E160K, E160V,
226 7 A226V,
230 8
222 8
217 8
164 8
208 8 A208V,
221 9
225 10 S225L, S225del,
156 10
207 10 V207M, V207L, V207L, V207L, V207L, V207del,
206 10 V206L,
219 10 G219E,
162 10 V162M,
229 10 G229D,
233 10 L233P,
165 11 V165M,
163 11
218 11
159 11 M159del,
227 11
158 11
205 11 V205M,
154 12
153 12 T153M,
223 12
234 12 Q234H, Q234H,
237 12
224 13 T224M,
155 13
231 13 R231C, R231H, R231S,
167 13
228 14
136 14
220 14 Q220K,
168 14 G168R, G168R, G168R, G168R,
152 14
232 14
204 14 I204M, I204F,
140 15 S140G, S140R, S140R, S140R,
203 15 L203P,
166 15 F166V,