KCNQ1 Variant S253P Detail

We estimate the penetrance of LQTS for KCNQ1 S253P is 17%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. S253P is present in 1 alleles in gnomAD. S253P 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S253P around 17% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.86 1.0 -2 0.969 17
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.

S253P has 27 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
253 0 S253A, S253P,
252 3 G252R,
254 4 V254M, V254L, V254L,
249 7 R249S, R249S,
246 10
245 11 G245V,
248 11 W248C, W248C, W248R, W248R,
250 12 L250H, L250P,
261 12 E261K, E261D, E261D, E261G, E261Q,
351 12 F351L, F351L, F351L, F351S,
354 13
251 13 L251P, L251Q,
268 13 I268V, I268S,
355 13
260 13
258 13 H258P, H258N, H258R, H258Y,
339 14 F339del, F339S,
352 14
264 14
358 14 K358T,
262 14 L262P, L262R, L262V,
346 14
265 14 T265I,
242 14 D242N, D242Y,
257 15 I257V,
244 15
259 15 R259C, R259H, R259L, R259G,