KCNQ1 Variant G434R Detail

We estimate the penetrance of LQTS for KCNQ1 G434R is 9%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. G434R is present in 2 alleles in gnomAD. G434R 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 G434R around 9% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.77 0.04 -3 0.629 4
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: - 2 2 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.

G434R 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
434 0 G434R, G434R,
433 4 P433A,
435 4
432 5 T432I, T432A,
436 5
431 7 V431L, V431L,
437 7 M437V,
430 8
438 8
429 8 N429S,
439 8
428 9 D428G,
440 9
427 10
441 10 P441S,
426 11
442 11 H442R,
425 11 L425V,
443 11
424 12 K424T,
444 12 T444M, T444K,
423 13
445 13
422 13 K422T, K422R,
446 13 D446E, D446E, D446E, D446E, D446N,
421 14 K421N, K421N,
447 14 P447H,
420 14 K420E, K420N, K420N,
448 14 P448R, P448Q, P448L, P448S,
419 15
449 15 E449K,