KCNH2 Variant L433Q Detail

We estimate the penetrance of LQTS for KCNH2 L433Q is 43%. We are unaware of any observations of this variant in individuals. L433Q is not present in gnomAD. L433Q has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L433Q around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.71 0.892 -2 0.945 47
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.

L433Q 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
433 0
432 4
434 4
431 5 F431L, F431L, F431L,
435 5 E435X, E435G,
430 7
436 7 T436M,
429 8 A429V, A429P,
437 8
428 8 S428L, S428X, S428fsX,
438 8 E438X, E438K,
427 9 Y427H, Y427C, Y427S,
439 9
426 10 P426H,
440 10 P440L,
425 11
441 11 P441R, P441L,
424 11
442 11
423 12
443 12 T443fsX, T443N,
422 13 A422T,
444 13 E444D, E444K, E444D,
421 13 T421fsX, T421M,
445 13
420 14 Y420C,
446 14
419 14
447 14 Y447X,
418 15
448 15 A448S, A448T,