KCNQ1 Variant L134M Detail

We estimate the penetrance of LQTS for KCNQ1 L134M is 63%. We are unaware of any observations of this variant in individuals. L134M is not present in gnomAD. L134M 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L134M around 63% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.54 0.99 1 0.76 68
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 4 6 -
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.

L134M has 46 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
134 0 L134P,
133 4 V133I,
135 5
130 5
137 5 L137F, L137P,
131 5
138 7
132 7 I132L,
136 7
238 7 M238V, M238L, M238L,
129 9 V129I,
128 9 A128del,
139 9
127 10 F127L, F127L, F127L,
234 10 Q234H, Q234H,
237 10
235 10 I235N,
241 10 V241F, V241I, V241G,
140 11 S140G, S140R, S140R, S140R,
274 11 I274V,
141 11 V141M,
267 12 Y267C,
271 12
239 12
240 12 H240R, H240P,
159 12 M159del,
270 12 F270S,
163 12
142 13
236 13 L236Q, L236R,
126 13 H126D,
160 14 E160del, E160K, E160V,
299 14
156 14
167 14
303 14 L303P,
275 14 F275del,
233 14 L233P,
125 14
123 14
273 14 L273F, L273V, L273R,
242 14 D242N, D242Y,
124 14
231 15 R231C, R231H, R231S,
143 15 S143F, S143P, S143Y,
230 15