KCNQ1 Variant L137R Detail

We estimate the penetrance of LQTS for KCNQ1 L137R is 29%. We are unaware of any observations of this variant in individuals. L137R is not present in gnomAD. L137R 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L137R around 29% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.38 1.0 -4 0.958 32
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 8 2 -
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.

L137R has 61 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
137 0 L137F, L137P,
136 4
138 5
134 5 L134P,
234 5 Q234H, Q234H,
140 6 S140G, S140R, S140R, S140R,
133 6 V133I,
135 6
235 7 I235N,
141 7 V141M,
238 7 M238V, M238L, M238L,
139 7
237 8
274 9 I274V,
299 9
130 9
132 9 I132L,
231 9 R231C, R231H, R231S,
142 10
131 10
233 10 L233P,
236 10 L236Q, L236R,
143 10 S143F, S143P, S143Y,
230 10
156 10
303 11 L303P,
159 11 M159del,
160 11 E160del, E160K, E160V,
275 11 F275del,
232 11
144 11 T144A,
271 11
239 12
278 12 Y278H,
300 12 A300T, A300S,
163 12
129 12 V129I,
277 12 S277L, S277del, S277P, S277W,
229 12 G229D,
240 12 H240R, H240P,
273 13 L273F, L273V, L273R,
152 13
145 13
241 13 V241F, V241I, V241G,
270 13 F270S,
155 14
128 14 A128del,
267 14 Y267C,
272 14 G272D, G272S, G272V,
302 14 A302V, A302E, A302T,
205 14 V205M,
167 14
298 14 S298I, S298N,
281 14 Y281C,
148 14
276 14 S276del,
209 15 S209P,
226 15 A226V,
127 15 F127L, F127L, F127L,
164 15
153 15 T153M,