KCNQ1 Variant P343S Detail

We estimate the penetrance of LQTS for KCNQ1 P343S is 83%. This variant was found in a total of 5 carriers in 5 papers or gnomAD, 5 had LQTS. P343S is not present in gnomAD. P343S 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 P343S around 83% (12/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.61 1.0 -1 0.913 84
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
23631430 2013 1 None None None
19490272 2009 1 None 1 None
17470695 2007 1 None 1 None
15511625 2004 3 None 3 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)
15511625 Oocytes 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)
15511625 Oocytes 40 None None None

P343S 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
341 10 A341V, A341E,
338 10 S338F,
345 10 G345R, G345R, G345A,
342 10 L342F, L342P,
344 11 A344V, A344E,
343 12 P343S, P343L, P343R,
251 12 L251P, L251Q,
335 12 F335L, F335L, F335L,
346 12
265 13 T265I,
337 13
348 13
334 13 V334A,
262 13 L262P, L262R, L262V,
339 13 F339del, F339S,
349 13 S349W,
268 14 I268V, I268S,
347 14 L347P, L347R,
340 14 F340del, F340L, F340L, F340L, F340S,
252 14 G252R,
266 14 L266P,
336 14 A336S,
264 14
250 15 L250H, L250P,
261 15 E261K, E261D, E261D, E261G, E261Q,
310 15 V310I,