KCNH2 Variant E444D Detail

We estimate the penetrance of LQTS for KCNH2 E444D is 36%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 2 had LQTS. E444D is not present in gnomAD. E444D 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E444D around 36% (4/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.492 0.0 4 0.496 41
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
12442276 2002 2 0 2
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
VARIANT FEATURES ALONE: - 10 8 2 -
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.

E444D 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
444 0 E444D, E444K, E444D,
443 4 T443N, T443fsX,
445 4
442 5
446 5
441 7 P441R, P441L,
447 7 Y447X,
440 8 P440L,
448 8 A448S, A448T,
439 8
449 8
438 9 E438X, E438K,
450 9
437 10
451 10 P451L,
436 11 T436M,
452 11
435 11 E435G, E435X,
453 11
434 12
454 12
433 13
455 13
432 13
456 13 D456Y,
431 14 F431L, F431L, F431L,
457 14 L457P,
430 14
458 14
429 15 A429V, A429P,
459 15