KCNQ1 Variant K393N Detail

We estimate the penetrance of LQTS for KCNQ1 K393N is 5%. This variant was found in a total of 303 carriers in 9 papers or gnomAD, 11 had LQTS. K393N is present in 290 alleles in gnomAD. K393N 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K393N around 5% (16/313).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.25 0.77 -1 0.554 51
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
33552729 2021 1 1 0 DCM
32470535 2020 1 None 1 None
30816480 2019 1 None None Large vessel ischemic stroke
29197658 2018 8 None 8 None
23571586 2013 1 1 None None
22949429 2012 3 3 None None
19841300 2009 3 3 None None
17470695 2007 10 None 10 None
14678125 2003 2 None 2 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)
16556865 CHO 100 13.3 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)
16556865 CHO None None None

K393N has 17 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
393 0 K393N,
394 5 I394L,
390 6
391 7 T391A, T391I,
392 8 W392R, W392R, W392ins,
389 9 S389P,
388 12 D388H, D388N,
380 12 R380S, R380S, R380G,
387 12 P387T,
514 12 I514T,
383 12
518 12 R518Q, R518G,
511 12 R511Q, R511W,
386 13 N386K, N386K,
510 13 H510R, H510Y,
384 13
379 13 W379R, W379R, W379C, W379C, W379G,