KCNQ1 Variant K358T Detail

We estimate the penetrance of LQTS for KCNQ1 K358T is 61%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. K358T is present in 1 alleles in gnomAD. K358T 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 K358T around 61% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.12 0.977 3 0.914 69
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.

K358T has 19 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
257 12 I257V,
359 12 Q359del,
258 12 H258P, H258N, H258R, H258Y,
363 13 H363N,
254 13 V254M, V254L, V254L,
264 13
260 13
249 14 R249S, R249S,
261 14 E261K, E261D, E261D, E261G, E261Q,
246 14
535 14
256 14
263 14
247 14 T247I,
253 15 S253A, S253P,
357 15 Q357H, Q357H,
364 15 F364L, F364L, F364L, F364S,
353 15 L353P,
259 15 R259C, R259H, R259L, R259G,