KCNQ1 Variant N483K Detail

We estimate the penetrance of LQTS for KCNQ1 N483K is 11%. We are unaware of any observations of this variant in individuals. N483K is not present in gnomAD. N483K has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N483K around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.06 0.027 0 0.612 6
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 9 1 -
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.

N483K has 31 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
483 0
482 4 T482N, T482A, T482S, T482S,
484 4
481 5
485 5 F485S,
480 7 M480T,
486 7 A486T,
479 8 F479L, F479L, F479L,
487 8 E487K,
478 8 H478Y,
488 8 D488E, D488E,
477 9 P477L, P477T,
489 9
476 10 M476L, M476L, M476V,
490 10
475 11
491 11
474 11
492 11 L492ins,
473 12 E473Q,
493 12 G493A,
472 13 L472P,
494 13
471 13
495 13 T495S, T495S, T495A,
470 14
496 14
469 14
497 14 L497P,
468 15 S468G, S468N,
498 15