KCNH2 Variant P440S Detail

We estimate the penetrance of LQTS for KCNH2 P440S is 9%. We are unaware of any observations of this variant in individuals. P440S is not present in gnomAD. P440S has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P440S around 9% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.466 0.09 0 0.573 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 LQT2 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.

P440S 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 since the functional KV11.1 channel (protein product of KCNH2/hERG) 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
440 0 P440L,
439 4
441 4 P441R, P441L,
438 5 E438X, E438K,
442 5
437 7
443 7 T443fsX, T443N,
436 8 T436M,
444 8 E444D, E444K, E444D,
435 8 E435X, E435G,
445 8
434 9
446 9
433 10
447 10 Y447X,
432 11
448 11 A448S, A448T,
431 11 F431L, F431L, F431L,
449 11
430 12
450 12
429 13 A429V, A429P,
451 13 P451L,
428 13 S428L, S428X, S428fsX,
452 13
427 14 Y427H, Y427C, Y427S,
453 14
426 14 P426H,
454 14
425 15
455 15