KCNH2 Variant I560N Detail

We estimate the penetrance of LQTS for KCNH2 I560N is 56%. We are unaware of any observations of this variant in individuals. I560N is not present in gnomAD. I560N 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 I560N around 56% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.695 0.992 -4 0.928 54
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.

I560N has 58 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
560 0 I560fsX, I560M,
561 4 A561P, A561V, A561T,
559 5 L559H, L559F,
558 5 A558E, A558P, A558V,
563 6 W563C, W563X, W563G, W563C,
557 6
556 6
564 6 L564L,
562 7 H562Q, H562R, H562P, H562Q,
651 8 M651K,
622 8 L622F,
647 8
618 8 T618S, T618S,
619 9
555 9
648 9 G648A,
565 9
644 10 V644I, V644F,
655 10
422 10 A422T,
615 10 L615F, L615V,
554 10
566 11 C566S, C566S, C566R, C566F, C566G,
553 11 L553V,
567 11 I567T, I567M,
423 11
621 11 S621R, S621R, S621N, S621R,
650 12 L650X,
623 12 T623I,
643 12
652 12 Y652X,
552 12 L552S,
646 12
656 12 F656L, F656L, F656L,
426 12 P426H,
640 12 F640L, F640L, F640L, F640V, F640Del,
419 12
532 12
654 13
649 13
529 13
620 13 S620I, S620G,
614 13 A614V, A614T,
617 13 F617L, F617L, F617L, F617V,
646 13
642 13 I642Del, I642V,
611 13 Y611D,
645 14 M645R, M645L, M645I, M645I, M645L, M645I, M645V,
653 14
649 14
568 14 W568C, W568C,
645 14 M645R, M645L, M645I, M645I, M645L, M645I, M645V,
551 14 F551L, F551L, F551L,
641 14 S641P, S641F,
421 14 T421M, T421fsX,
425 14
418 15
624 15 S624R, S624R, S624R, S624N,