KCNQ1 Variant L342F Detail

We estimate the penetrance of LQTS for KCNQ1 L342F is 85%. This variant was found in a total of 6 carriers in 7 papers or gnomAD, 6 had LQTS. L342F is not present in gnomAD. L342F has been functionally characterized in 1 papers. 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 L342F around 85% (13/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.66 1.0 1 0.876 85
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
32893267 2020 1 None 1 None
27041096 2016 1 None 1 None
24217263 2013 1 None 1 None
19716085 2009 2 None 2 None
18752142 2008 4 None 1 RWS
17192539 2006 1 None 1 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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
9312006 COS 0 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
9312006 COS 55 0.0 None 0.8552822

L342F 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
344 8 A344V, A344E,
345 8 G345R, G345R, G345A,
348 9
341 10 A341V, A341E,
347 10 L347P, L347R,
343 10 P343S, P343L, P343R,
342 11 L342F, L342P,
346 11
349 11 S349W,
351 12 F351L, F351L, F351L, F351S,
350 13 G350V, G350R, G350R, G350W,
338 13 S338F,
251 13 L251P, L251Q,
352 13
247 14 T247I,
254 14 V254M, V254L, V254L,
255 14
252 14 G252R,
262 14 L262P, L262R, L262V,
340 14 F340del, F340L, F340L, F340L, F340S,
263 14
337 15
257 15 I257V,
271 15
266 15 L266P,
258 15 H258P, H258N, H258R, H258Y,