KCNQ1 Variant S349W Detail

We estimate the penetrance of LQTS for KCNQ1 S349W is 84%. This variant was found in a total of 2 carriers in 8 papers or gnomAD, 2 had LQTS. S349W is not present in gnomAD. S349W 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 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S349W around 84% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.49 1.0 -4 0.95 93
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
33614747 2021 1 None 1 None
25471708 2015 1 None None JLNS w/ vestibular DFx
23153844 2012 15 None 1 None
22539601 2012 1 None None None
20662986 2011 None None None None
19490272 2009 15 None 15 None
17470695 2007 15 None 15 None
14678125 2003 10 None 10 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)
20662986 Oocytes 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)
20662986 Oocytes 125 18.0 1.4 1.0

S349W 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
349 6 S349W,
348 8
345 8 G345R, G345R, G345A,
352 8
350 9 G350V, G350R, G350R, G350W,
353 9 L353P,
346 10
344 11 A344V, A344E,
347 11 L347P, L347R,
351 11 F351L, F351L, F351L, F351S,
342 12 L342F, L342P,
356 13
355 13
258 13 H258P, H258N, H258R, H258Y,
343 13 P343S, P343L, P343R,
341 14 A341V, A341E,
354 14
357 15 Q357H, Q357H,
254 15 V254M, V254L, V254L,