KCNQ1 Variant P447H Detail

We estimate the penetrance of LQTS for KCNQ1 P447H is 10%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. P447H is present in 1 alleles in gnomAD. P447H 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 P447H around 10% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.05 0.0 -1 0.611 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
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.

P447H 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
447 0 P447H,
446 4 D446E, D446E, D446E, D446E, D446N,
448 4 P448R, P448Q, P448L, P448S,
445 5
449 5 E449K,
444 7 T444M, T444K,
450 7 E450K,
443 8
451 8 R451Q, R451W,
442 8 H442R,
452 8 R452Q, R452W, R452L,
441 9 P441S,
453 9
440 10
454 10
439 11
455 11 H455Y, H455Q, H455Q, H455R,
438 11
456 11 F456L, F456L, F456L,
437 12 M437V,
457 12
436 13
458 13
435 13
459 13 D459N, D459V,
434 14 G434R, G434R,
460 14 G460S, G460D, G460C,
433 14 P433A,
461 14
432 15 T432I, T432A,
462 15