KCNQ1 Variant K183R Detail

We estimate the penetrance of LQTS for KCNQ1 K183R is 69%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. K183R is not present in gnomAD. K183R 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 K183R around 69% (7/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.93 0.356 1 0.819 79
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
32893267 2020 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.

K183R has 31 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
183 0 K183R,
184 4 Y184S, Y184C, Y184D, Y184H,
181 5 R181C,
182 5
192 6 R192C, R192H,
189 7 G189R, G189R, G189E,
185 8 V185L, V185L, V185M, V185del,
193 8 F193L, F193L, F193L,
188 8 W188C, W188C, W188G, W188S,
178 9 A178T, A178del,
179 9 G179S,
180 10
196 10
190 10 R190W, R190Q, R190L,
186 10 G186R, G186D,
111 11 Y111C,
195 11 R195Q, R195W,
191 11
194 11 A194P, A194T,
177 12 S177F,
244 12
116 13
115 13 E115A, E115G,
187 13 L187P, L187F,
175 13 L175I,
199 14 S199A,
197 14 P197L,
108 14 G108S,
112 14
174 15 R174H, R174C, R174L,
198 15 I198V, I198T,