KCNQ1 Variant L175I Detail

We estimate the penetrance of LQTS for KCNQ1 L175I is 28%. This variant was found in a total of 3 carriers in 0 papers or gnomAD, 0 had LQTS. L175I is present in 3 alleles in gnomAD. L175I has not been functionally characterized. 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L175I around 28% (3/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.84 0.78 2 0.708 37
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: - 3 3 0
VARIANT FEATURES ALONE: - 10 7 3 -
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.

L175I 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
175 0 L175I,
172 5 V172M, V172E,
190 5 R190W, R190Q, R190L,
171 5
176 6
193 6 F193L, F193L, F193L,
173 6
177 6 S177F,
174 6 R174H, R174C, R174L,
178 7 A178T, A178del,
194 8 A194P, A194T,
199 9 S199A,
179 9 G179S,
189 9 G189R, G189R, G189E,
191 9
170 9
184 9 Y184S, Y184C, Y184D, Y184H,
168 10 G168R, G168R, G168R, G168R,
111 10 Y111C,
186 10 G186R, G186D,
169 10 T169M, T169R,
187 10 L187P, L187F,
114 10
203 10 L203P,
115 11 E115A, E115G,
107 11 Q107H, Q107H,
202 11 D202N, D202H,
110 11 V110I,
180 11
196 12
185 12 V185L, V185L, V185M, V185del,
181 12 R181C,
200 12
195 12 R195Q, R195W,
198 12 I198V, I198T,
192 13 R192C, R192H,
188 13 W188C, W188C, W188G, W188S,
108 13 G108S,
206 13 V206L,
183 13 K183R,
243 13 R243H, R243C, R243P, R243S,
167 13
197 14 P197L,
112 14
201 14 I201del,
113 14
166 14 F166V,
244 14
182 15
240 15 H240R, H240P,
106 15
204 15 I204M, I204F,