KCNQ1 Variant G252R Detail

We estimate the penetrance of LQTS for KCNQ1 G252R is 26%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. G252R is present in 1 alleles in gnomAD. G252R 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 G252R around 26% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.78 0.988 -1 0.931 31
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
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.

G252R has 34 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
252 0 G252R,
253 3 S253A, S253P,
251 5 L251P, L251Q,
254 5 V254M, V254L, V254L,
256 7
249 7 R249S, R249S,
248 9 W248C, W248C, W248R, W248R,
246 10
245 10 G245V,
268 10 I268V, I268S,
339 11 F339del, F339S,
261 13 E261K, E261D, E261D, E261G, E261Q,
335 13 F335L, F335L, F335L,
338 13 S338F,
242 13 D242N, D242Y,
264 13
262 13 L262P, L262R, L262V,
265 13 T265I,
269 14 G269D, G269S, G269del,
258 14 H258P, H258N, H258R, H258Y,
260 14
346 14
255 14
342 14 L342F, L342P,
263 14
351 14 F351L, F351L, F351L, F351S,
197 15 P197L,
244 15
343 15 P343S, P343L, P343R,
259 15 R259C, R259H, R259L, R259G,
355 15
352 15
336 15 A336S,
271 15