KCNQ1 Variant L347P Detail

We estimate the penetrance of LQTS for KCNQ1 L347P is 76%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. L347P is not present in gnomAD. L347P 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 L347P around 76% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.21 1.0 -4 0.919 80
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
26496715 2016 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
VARIANT FEATURES ALONE: - 10 3 7 -
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.

L347P 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
348 8
345 9 G345R, G345R, G345A,
349 9 S349W,
347 9 L347P, L347R,
344 10 A344V, A344E,
352 10
351 10 F351L, F351L, F351L, F351S,
350 11 G350V, G350R, G350R, G350W,
346 11
343 12 P343S, P343L, P343R,
353 12 L353P,
266 13 L266P,
342 13 L342F, L342P,
254 13 V254M, V254L, V254L,
264 13
341 13 A341V, A341E,
263 13
260 13
250 13 L250H, L250P,
259 14 R259C, R259H, R259L, R259G,
258 14 H258P, H258N, H258R, H258Y,
355 14
251 14 L251P, L251Q,
255 14
354 14
256 14
262 15 L262P, L262R, L262V,