KCNH2 Variant I567M Detail

We estimate the penetrance of LQTS for KCNH2 I567M is 22%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. I567M is present in 1 alleles in gnomAD. I567M 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I567M around 22% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.925 1.0 1 0.884 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: - 1 1 0 -
VARIANT FEATURES ALONE: - 10 8 2 -
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.

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