KCNQ1 Variant I161L Detail

We estimate the penetrance of LQTS for KCNQ1 I161L is 55%. We are unaware of any observations of this variant in individuals. I161L is not present in gnomAD. I161L 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I161L around 55% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.41 0.124 2 0.7 64
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 5 5 -
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.

I161L 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
161 0
162 5 V162M,
160 5 E160del, E160K, E160V,
164 6
213 6
157 6 F157C,
158 6
165 7 V165M,
163 7
159 7 M159del,
209 8 S209P,
156 9
214 9 C214Y,
210 9 M210I, M210I, M210I,
216 10 G216R,
212 10
154 10
155 11
167 11
166 11 F166V,
206 11 V206L,
230 11
217 11
211 11
168 12 G168R, G168R, G168R, G168R,
208 12 A208V,
215 12 V215M, V215G, V215L, V215L,
237 12
136 12
226 12 A226V,
153 12 T153M,
234 13 Q234H, Q234H,
207 13 V207M, V207L, V207L, V207L, V207L, V207del,
205 13 V205M,
233 13 L233P,
169 13 T169M, T169R,
222 13
152 13
132 14 I132L,
139 14
229 14 G229D,
133 15 V133I,
218 15
225 15 S225L, S225del,