KCNH2 Variant D411E Detail

We estimate the penetrance of LQTS for KCNH2 D411E is 18%. We are unaware of any observations of this variant in individuals. D411E is not present in gnomAD. D411E 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 D411E around 18% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.8 1.0 1 0.886 26
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.

D411E has 52 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
411 0
408 5
407 5
414 5 I414fsX,
410 5 W410X,
412 6 W412X,
541 6 R541H, R541C,
538 6
409 6 V409L, V409L, V409M,
542 7
413 7 L413P,
415 7
535 9 V535M,
534 9 R534C,
406 9
466 9 D466E, D466E,
537 10 R537W,
404 10
540 10 D540fsX,
416 10
417 10
405 10
469 11
539 11
418 11
470 11 N470D,
402 11 H402R,
3 11
536 11 A536X,
462 11 M462Ins,
463 12 F463L, F463L, F463L,
544 12 E544fsX, E544A,
473 12 T473P,
543 12 S543fsX,
465 13
532 13
533 13
401 13
545 13
403 13
419 13
400 13 I400N,
474 13 T474I,
548 13
552 13 L552S,
467 14
531 14 R531W, R531Q, R531Del,
501 14 D501Y, D501N, D501H,
551 15 F551L, F551L, F551L,
459 15
497 15 W497L, W497X,
468 15 L468R, L468X, L468F,