KCNQ1 Variant M159I Detail

We estimate the penetrance of LQTS for KCNQ1 M159I is 82%. We are unaware of any observations of this variant in individuals. M159I is not present in gnomAD. M159I 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 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 M159I around 82% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.11 0.302 3 0.738 88
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 2 8 -
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.

M159I has 50 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
159 0 M159del,
156 5
160 5 E160del, E160K, E160V,
158 5
163 6
155 6
162 6 V162M,
136 6
161 7
139 8
132 8 I132L,
135 8
157 8 F157C,
154 8
152 9
164 9
133 10 V133I,
234 10 Q234H, Q234H,
153 11 T153M,
140 11 S140G, S140R, S140R, S140R,
237 11
166 11 F166V,
137 11 L137F, L137P,
167 11
165 11 V165M,
230 11
213 11
138 11
129 12 V129I,
209 12 S209P,
134 12 L134P,
143 12 S143F, S143P, S143Y,
151 12
131 13
142 13
233 13 L233P,
128 13 A128del,
149 14
231 14 R231C, R231H, R231S,
141 14 V141M,
226 14 A226V,
130 14
212 14
206 14 V206L,
205 14 V205M,
216 15 G216R,
217 15
168 15 G168R, G168R, G168R, G168R,
150 15 A150T,
235 15 I235N,