KCNQ1 Variant N386K Detail

We estimate the penetrance of LQTS for KCNQ1 N386K is 17%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. N386K is present in 2 alleles in gnomAD. N386K has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N386K around 17% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.48 0.065 0 0.58 22
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
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.

N386K has 23 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
386 0 N386K, N386K,
387 4 P387T,
389 5 S389P,
388 5 D388H, D388N,
383 5
385 6 E385K,
384 6
392 7 W392R, W392R, W392ins,
382 8
391 8 T391A, T391I,
390 9
379 10 W379R, W379R, W379C, W379C, W379G,
511 11 R511Q, R511W,
381 11 C381Y,
515 11
518 12 R518Q, R518G,
380 13 R380S, R380S, R380G,
393 13 K393N,
514 13 I514T,
378 13 A378T,
508 14 E508G,
512 14
510 15 H510R, H510Y,