KCNH2 Variant E438V Detail

We estimate the penetrance of LQTS for KCNH2 E438V is 11%. We are unaware of any observations of this variant in individuals. E438V is not present in gnomAD. E438V 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E438V around 11% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.926 0.23 -2 0.535 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 9 1 -
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.

E438V 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
438 0 E438K, E438X,
437 4
439 4
436 5 T436M,
440 5 P440L,
435 7 E435X, E435G,
441 7 P441R, P441L,
434 8
442 8
433 8
443 8 T443fsX, T443N,
432 9
444 9 E444D, E444D, E444K,
431 10 F431L, F431L, F431L,
445 10
430 11
446 11
429 11 A429P, A429V,
447 11 Y447X,
428 12 S428fsX, S428L, S428X,
448 12 A448S, A448T,
427 13 Y427H, Y427C, Y427S,
449 13
426 13 P426H,
450 13
425 14
451 14 P451L,
424 14
452 14
423 15
453 15