KCNQ1 Variant R249S Detail

We estimate the penetrance of LQTS for KCNQ1 R249S is 28%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. R249S is present in 2 alleles in gnomAD. R249S 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R249S around 28% (3/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.34 0.974 -1 0.782 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
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.

R249S 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
249 0 R249S, R249S,
245 5 G245V,
246 5
250 7 L250H, L250P,
253 7 S253A, S253P,
252 7 G252R,
247 7 T247I,
248 7 W248C, W248C, W248R, W248R,
244 8
251 9 L251P, L251Q,
242 9 D242N, D242Y,
254 10 V254M, V254L, V254L,
196 11
264 11
197 11 P197L,
198 12 I198V, I198T,
243 12 R243H, R243C, R243P, R243S,
268 12 I268V, I268S,
354 13
351 13 F351L, F351L, F351L, F351S,
267 13 Y267C,
116 13
265 14 T265I,
115 14 E115A, E115G,
241 14 V241F, V241I, V241G,
239 14