KCNQ1 Variant L353P Detail

We estimate the penetrance of LQTS for KCNQ1 L353P is 88%. This variant was found in a total of 8 carriers in 6 papers or gnomAD, 8 had LQTS. L353P is not present in gnomAD. L353P 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L353P around 88% (15/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.62 0.996 -3 0.968 92
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 2 None 2 None
27041096 2016 2 None 2 None
22949429 2012 1 None 1 None
19841300 2009 1 None 1 None
19490272 2009 4 None 4 None
17470695 2007 4 None 4 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.

L353P has 16 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
353 8 L353P,
352 9
349 9 S349W,
356 10
350 10 G350V, G350R, G350R, G350W,
348 11
355 12
357 12 Q357H, Q357H,
345 13 G345R, G345R, G345A,
354 13
351 13 F351L, F351L, F351L, F351S,
346 13
359 14 Q359del,
360 14 R360ins, R360G, R360M,
258 14 H258P, H258N, H258R, H258Y,
347 14 L347P, L347R,