KCNQ1 Variant G186R Detail

We estimate the penetrance of LQTS for KCNQ1 G186R is 61%. This variant was found in a total of 14 carriers in 2 papers or gnomAD, 12 had LQTS. G186R is not present in gnomAD. G186R 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G186R around 61% (14/24).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.08 1.0 0 0.951 42
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
20186784 2010 13 2 11 None
19841300 2009 1 None 1 None
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.

G186R has 26 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
186 0 G186R, G186D,
185 4 V185L, V185L, V185M, V185del,
190 5 R190W, R190Q, R190L,
187 5 L187P, L187F,
189 5 G189R, G189R, G189E,
188 5 W188C, W188C, W188G, W188S,
179 7 G179S,
191 8
184 8 Y184S, Y184C, Y184D, Y184H,
178 8 A178T, A178del,
192 9 R192C, R192H,
182 10
175 10 L175I,
193 10 F193L, F193L, F193L,
183 10 K183R,
177 11 S177F,
180 11
181 11 R181C,
176 11
194 12 A194P, A194T,
195 13 R195Q, R195W,
107 13 Q107H, Q107H,
172 14 V172M, V172E,
111 14 Y111C,
173 15
171 15