KCNH2 Variant Y652H Detail

We estimate the penetrance of LQTS for KCNH2 Y652H is 54%. We are unaware of any observations of this variant in individuals. Y652H is not present in gnomAD. Y652H 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 Y652H around 54% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.842 1.0 2 0.927 68
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.

Y652H has 81 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
652 0 Y652X,
656 5 F656L, F656L, F656L,
653 5
623 6 T623I,
648 7 G648A,
649 7
651 7 M651K,
649 7
622 7 L622F,
655 7
624 7 S624R, S624N, S624R, S624R,
654 8
653 8
557 8
650 9 L650X,
657 9 G657V, G657S,
652 9 Y652X,
652 9 Y652X,
648 10 G648A,
624 10 S624R, S624N, S624R, S624R,
650 10 L650X,
656 10 F656L, F656L, F656L,
623 10 T623I,
624 10 S624R, S624N, S624R, S624R,
659 10
647 10
621 10 S621R, S621R, S621R, S621N,
619 11
646 11
645 11 M645V, M645I, M645I, M645R, M645L, M645L, M645I,
625 11 V625E,
660 11 S660L,
554 11
658 11
620 11 S620G, S620I,
660 11 S660L,
645 12 M645V, M645I, M645I, M645R, M645L, M645L, M645I,
625 12 V625E,
644 12 V644F, V644I,
553 12 L553V,
624 12 S624R, S624N, S624R, S624R,
560 12 I560M, I560fsX,
654 12
646 12
623 12 T623I,
653 12
657 12 G657V, G657S,
651 12 M651K,
652 13 Y652X,
659 13
622 13 L622F,
647 13
618 13 T618S, T618S,
556 13
558 13 A558V, A558P, A558E,
656 13 F656L, F656L, F656L,
561 13 A561T, A561V, A561P,
657 13 G657V, G657S,
621 13 S621R, S621R, S621R, S621N,
625 14 V625E,
626 14 G626S, G626V, G626A,
653 14
644 14 V644F, V644I,
622 14 L622F,
655 14
661 14 A661V,
655 14
625 14 V625E,
663 14
642 14 I642V, I642Del,
550 15
623 15 T623I,
649 15
620 15 S620G, S620I,
557 15
649 15
554 15
648 15 G648A,
555 15
643 15
626 15 G626S, G626V, G626A,