KCNH2 Variant H562D Detail

We estimate the penetrance of LQTS for KCNH2 H562D is 54%. We are unaware of any observations of this variant in individuals. H562D is not present in gnomAD. H562D 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 H562D around 54% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.626 0.999 -1 0.923 60
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 5 5 -
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.

H562D has 62 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
562 0 H562R, H562Q, H562Q, H562P,
561 5 A561V, A561T, A561P,
563 5 W563C, W563X, W563G, W563C,
559 5 L559H, L559F,
566 6 C566S, C566F, C566G, C566R, C566S,
423 6
565 6
558 6 A558E, A558V, A558P,
611 7 Y611D,
615 7 L615F, L615V,
426 7 P426H,
564 7 L564L,
422 7 A422T,
560 7 I560fsX, I560M,
427 8 Y427H, Y427C, Y427S,
614 9 A614T, A614V,
618 9 T618S, T618S,
424 9
567 9 I567T, I567M,
619 10
425 10
431 10 F431L, F431L, F431L,
612 10 V612A, V612L, V612L,
557 10
556 10
419 11
430 11
555 11
428 11 S428X, S428L, S428fsX,
421 11 T421M, T421fsX,
569 11 Y569H, Y569C, Y569X,
429 12 A429V, A429P,
529 12
642 12 I642V, I642Del,
568 12 W568C, W568C,
420 12 Y420C,
613 12 T613L, T613M, T613A, T613K,
617 12 F617V, F617L, F617L, F617L,
622 12 L622F,
570 13
616 13 Y616S,
610 13
608 13
418 13
646 14
640 14 F640L, F640L, F640V, F640Del, F640L,
644 14 V644I, V644F,
639 14 I639F, I639N,
609 14 D609G, D609N,
607 14
554 14
532 14
526 14
620 14 S620G, S620I,
621 14 S621R, S621R, S621R, S621N,
432 15
645 15 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
647 15
571 15 I571L, I571V,
651 15 M651K,
638 15 K638R, K638Del, K638E, K638D,
528 15 R528P, R528X, R528W,