KCNH2 Variant I567N Detail

We estimate the penetrance of LQTS for KCNH2 I567N is 36%. We are unaware of any observations of this variant in individuals. I567N is not present in gnomAD. I567N 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I567N around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.746 1.0 -4 0.924 35
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 7 3 -
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.

I567N has 59 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
567 0 I567M, I567T,
566 5 C566G, C566F, C566S, C566S, C566R,
564 5 L564L,
565 6
570 6
568 7 W568C, W568C,
571 7 I571V, I571L,
640 7 F640L, F640Del, F640L, F640L, F640V,
569 8 Y569H, Y569C, Y569X,
563 8 W563G, W563C, W563C, W563X,
430 9
562 9 H562P, H562R, H562Q, H562Q,
561 9 A561T, A561V, A561P,
426 9 P426H,
614 9 A614T, A614V,
618 9 T618S, T618S,
572 10 G572D, G572R, G572C, G572S,
644 10 V644I, V644F,
643 10
431 10 F431L, F431L, F431L,
574 10 M574V, M574L, M574L,
573 11
617 11 F617L, F617L, F617V, F617L,
429 11 A429P, A429V,
560 11 I560M, I560fsX,
637 11 E637G, E637X, E637K,
636 11
615 11 L615F, L615V,
611 11 Y611D,
585 11 W585C, W585C,
641 11 S641P, S641F,
639 12 I639F, I639N,
427 12 Y427S, Y427H, Y427C,
559 12 L559F, L559H,
575 13 E575K,
647 13
425 13
526 13
613 13 T613L, T613A, T613K, T613M,
610 13
621 13 S621R, S621R, S621R, S621N,
428 13 S428fsX, S428X, S428L,
422 13 A422T,
523 13
622 13 L622F,
423 13
529 14
619 14
558 14 A558P, A558E, A558V,
642 14 I642V, I642Del,
586 14 L586M,
632 14 P632A, P632S,
634 14 T634S, T634I, T634S, T634A, T634P,
612 14 V612A, V612L, V612L,
638 14 K638E, K638Del, K638R, K638D,
432 14
645 15 M645I, M645I, M645R, M645I, M645L, M645V, M645L,
620 15 S620I, S620G,
630 15 V630A, V630T, V630I,