KCNQ1 Variant L163V Detail

We estimate the penetrance of LQTS for KCNQ1 L163V is 42%. We are unaware of any observations of this variant in individuals. L163V is not present in gnomAD. L163V 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 L163V around 42% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.03 0.637 2 0.789 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.

L163V has 57 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
163 0
162 4 V162M,
164 5
167 5
159 6 M159del,
160 6 E160del, E160K, E160V,
166 6 F166V,
165 7 V165M,
161 7
132 7 I132L,
237 8
136 8
158 8
133 9 V133I,
129 9 V129I,
168 9 G168R, G168R, G168R, G168R,
156 10
209 10 S209P,
234 10 Q234H, Q234H,
206 10 V206L,
169 10 T169M, T169R,
170 10
135 11
205 11 V205M,
213 11
157 11 F157C,
233 11 L233P,
230 12
128 12 A128del,
155 12
240 12 H240R, H240P,
139 12
137 12 L137F, L137P,
130 12
131 12
125 12
134 12 L134P,
210 13 M210I, M210I, M210I,
202 13 D202N, D202H,
208 13 A208V,
154 13
140 14 S140G, S140R, S140R, S140R,
236 14 L236Q, L236R,
212 14
171 14
207 14 V207M, V207L, V207L, V207L, V207L, V207del,
238 14 M238V, M238L, M238L,
126 14 H126D,
235 14 I235N,
138 14
203 14 L203P,
152 15
241 15 V241F, V241I, V241G,
214 15 C214Y,
172 15 V172M, V172E,
174 15 R174H, R174C, R174L,
229 15 G229D,