KCNQ1 Variant L203I Detail

We estimate the penetrance of LQTS for KCNQ1 L203I is 71%. We are unaware of any observations of this variant in individuals. L203I is not present in gnomAD. L203I 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 L203I around 71% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.31 0.78 2 0.714 74
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.

L203I has 44 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
203 0 L203P,
204 5 I204M, I204F,
206 5 V206L,
202 5 D202N, D202H,
207 6 V207M, V207L, V207L, V207L, V207L, V207del,
171 6
200 6
205 6 V205M,
199 7 S199A,
201 7 I201del,
194 8 A194P, A194T,
168 9 G168R, G168R, G168R, G168R,
208 9 A208V,
209 10 S209P,
198 10 I198V, I198T,
210 10 M210I, M210I, M210I,
167 10
175 10 L175I,
172 10 V172M, V172E,
240 11 H240R, H240P,
164 11
197 11 P197L,
233 11 L233P,
174 11 R174H, R174C, R174L,
193 11 F193L, F193L, F193L,
170 11
236 12 L236Q, L236R,
237 12
196 12
169 12 T169M, T169R,
211 12
195 12 R195Q, R195W,
191 12
165 13 V165M,
239 13
173 14
243 14 R243H, R243C, R243P, R243S,
166 14 F166V,
190 14 R190W, R190Q, R190L,
212 14
232 14
163 14
176 15
213 15