KCNQ1 Variant G154R Detail

We estimate the penetrance of LQTS for KCNQ1 G154R is 45%. We are unaware of any observations of this variant in individuals. G154R is not present in gnomAD. G154R 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 G154R around 45% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.29 0.015 0 0.584 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.

G154R has 40 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
154 0
155 4
153 4 T153M,
152 5
157 5 F157C,
156 5
151 7
158 7
150 8 A150T,
149 8
159 8 M159del,
217 9
160 10 E160del, E160K, E160V,
161 10
143 10 S143F, S143P, S143Y,
139 10
213 12
216 12 G216R,
162 12 V162M,
140 12 S140G, S140R, S140R, S140R,
136 12
222 12
142 12
148 13
230 13
226 13 A226V,
218 13
163 13
146 14 E146K, E146G, E146Q,
227 14
144 14 T144A,
135 14
234 14 Q234H, Q234H,
212 14
231 14 R231C, R231H, R231S,
145 15
138 15
141 15 V141M,
164 15
147 15 Q147R,