KCNH2 Variant E544D Detail

We estimate the penetrance of LQTS for KCNH2 E544D is 66%. We are unaware of any observations of this variant in individuals. E544D is not present in gnomAD. E544D 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E544D around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.873 0.975 1 0.821 76
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 4 6 -
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.

E544D has 50 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
544 0 E544fsX, E544A,
545 5
543 5 S543fsX,
541 7 R541H, R541C,
540 7 D540fsX,
3 7
681 8 R681W,
542 8
546 8
548 9
674 9 H674fsX, H674Y,
677 9 M677T,
549 10 V549M,
539 10
412 10 W412X,
678 10
547 10 A547T,
408 10
673 11
698 11 E698X, E698K,
411 12
538 12
665 12 R665Q,
4 12
702 12
685 12 R685H, R685P, R685C,
680 13
409 13 V409L, V409L, V409M,
552 13 L552S,
5 13
694 13 R694H, R694C,
675 13
682 13 E682X,
666 13
403 13
405 13
402 13 H402R,
662 14
670 14
535 14 V535M,
550 14
407 14
404 14
684 14
551 14 F551L, F551L, F551L,
701 14
415 14
671 14 A671Del, A671G,
536 14 A536X,
676 15 Q676X, Q676fsX,