KCNH2 Variant A442P Detail

We estimate the penetrance of LQTS for KCNH2 A442P is 14%. We are unaware of any observations of this variant in individuals. A442P is not present in gnomAD. A442P has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A442P around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.132 0.014 -1 0.518 13
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.

A442P 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
442 0
441 4 P441R, P441L,
443 4 T443fsX, T443N,
440 5 P440L,
444 5 E444D, E444D, E444K,
439 7
445 7
438 8 E438K, E438X,
446 8
437 8
447 8 Y447X,
436 9 T436M,
448 9 A448T, A448S,
435 10 E435X, E435G,
449 10
434 11
450 11
433 11
451 11 P451L,
432 12
452 12
431 13 F431L, F431L, F431L,
453 13
430 13
454 13
429 14 A429V, A429P,
455 14
428 14 S428fsX, S428L, S428X,
456 14 D456Y,
427 15 Y427S, Y427H, Y427C,
457 15 L457P,