KCNQ1 Variant H442R Detail

We estimate the penetrance of LQTS for KCNQ1 H442R is 9%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. H442R is present in 1 alleles in gnomAD. H442R 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 H442R around 9% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.79 0.004 -1 0.606 2
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.

H442R 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
442 0 H442R,
441 4 P441S,
443 4
440 5
444 5 T444M, T444K,
439 7
445 7
438 8
446 8 D446E, D446E, D446E, D446E, D446N,
437 8 M437V,
447 8 P447H,
436 9
448 9 P448R, P448Q, P448L, P448S,
435 10
449 10 E449K,
434 11 G434R, G434R,
450 11 E450K,
433 11 P433A,
451 11 R451Q, R451W,
432 12 T432I, T432A,
452 12 R452Q, R452W, R452L,
431 13 V431L, V431L,
453 13
430 13
454 13
429 14 N429S,
455 14 H455Y, H455Q, H455Q, H455R,
428 14 D428G,
456 14 F456L, F456L, F456L,
427 15
457 15