KCNQ1 Variant K422R Detail

We estimate the penetrance of LQTS for KCNQ1 K422R is 15%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. K422R is present in 1 alleles in gnomAD. K422R 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K422R around 15% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.9 0.94 2 0.628 17
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: - 1 1 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.

K422R 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
422 0 K422T, K422R,
421 4 K421N, K421N,
423 4
420 5 K420E, K420N, K420N,
424 5 K424T,
419 7
425 7 L425V,
418 8 V418I,
426 8
417 8 V417M,
427 8
416 9 V416M,
428 9 D428G,
415 10
429 10 N429S,
414 11
430 11
413 11 K413R,
431 11 V431L, V431L,
412 12 P412S,
432 12 T432I, T432A,
411 13
433 13 P433A,
410 13
434 13 G434R, G434R,
409 14
435 14
408 14 P408A,
436 14
407 15
437 15 M437V,