KCNH2 Variant N573H Detail

We estimate the penetrance of LQTS for KCNH2 N573H is 71%. We are unaware of any observations of this variant in individuals. N573H is not present in gnomAD. N573H 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 N573H around 71% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.184 0.417 1 0.737 82
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 3 7 -
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.

N573H has 45 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
573 0
572 4 G572D, G572S, G572R, G572C,
570 5
569 5 Y569C, Y569X, Y569H,
574 5 M574V, M574L, M574L,
576 6
571 7 I571V, I571L,
575 7 E575K,
586 8 L586M,
430 9
585 9 W585C, W585C,
431 9 F431L, F431L, F431L,
610 9
568 10 W568C, W568C,
587 10
577 11
567 11 I567M, I567T,
566 11 C566S, C566F, C566S, C566G, C566R,
584 11 G584C, G584R, G584S,
432 11
637 11 E637K, E637G, E637X,
597 12 Y597C, Y597H,
605 12 P605L,
429 12 A429P, A429V,
607 12
636 12
565 12
614 12 A614V, A614T,
583 13 I583V,
634 13 T634P, T634I, T634S, T634A, T634S,
604 13 G604C, G604D, G604S,
589 13 L589P,
603 13 G603D,
606 14 S606Del, S606P, S606F,
613 14 T613A, T613K, T613M, T613L,
611 14 Y611D,
609 14 D609N, D609G,
427 14 Y427S, Y427C, Y427H,
640 14 F640L, F640Del, F640L, F640V, F640L,
588 14 N588K, N588K, N588D,
428 14 S428L, S428X, S428fsX,
590 14 G590V, G590D,
426 15 P426H,
523 15
564 15 L564L,