KCNH2 Variant Y616N Detail

We estimate the penetrance of LQTS for KCNH2 Y616N is 83%. We are unaware of any observations of this variant in individuals. Y616N is not present in gnomAD. Y616N 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y616N around 83% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.536 0.999 -2 0.944 89
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 2 8 -
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.

Y616N has 84 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
616 0 Y616S,
638 5 K638E, K638R, K638D, K638Del,
613 5 T613K, T613M, T613L, T613A,
617 6 F617L, F617L, F617V, F617L,
620 6 S620G, S620I,
641 6 S641P, S641F,
627 6 F627L, F627L, F627fsX, F627X, F627L,
632 6 P632S, P632A,
615 6 L615F, L615V,
642 6 I642V, I642Del,
614 7 A614T, A614V,
630 7 V630I, V630A, V630T,
612 7 V612A, V612L, V612L,
629 7 N629K, N629I, N629T, N629S, N629K, N629D,
619 8
618 8 T618S, T618S,
645 8 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
639 8 I639N, I639F,
626 9 G626V, G626A, G626S,
628 9 G628Del, G628D, G628V, G628R, G628S, G628A,
631 9 S631F,
633 9 N633S, N633I, N633D,
625 9 V625E,
621 9 S621R, S621R, S621R, S621N,
637 9 E637X, E637K, E637G,
635 10 N635I,
634 10 T634P, T634S, T634I, T634S, T634A,
611 10 Y611D,
609 10 D609G, D609N,
640 10 F640Del, F640L, F640L, F640L, F640V,
631 10 S631F,
565 10
623 11 T623I,
621 11 S621R, S621R, S621R, S621N,
568 11 W568C, W568C,
644 11 V644F, V644I,
636 11
585 11 W585C, W585C,
643 11
561 11 A561V, A561T, A561P,
622 11 L622F,
589 11 L589P,
627 11 F627L, F627L, F627fsX, F627X, F627L,
626 12 G626V, G626A, G626S,
617 12 F617L, F617L, F617V, F617L,
592 12 Q592X,
646 12
624 12 S624R, S624N, S624R, S624R,
630 12 V630I, V630A, V630T,
610 12
628 12 G628Del, G628D, G628V, G628R, G628S, G628A,
564 13 L564L,
632 13 P632S, P632A,
625 13 V625E,
568 13 W568C, W568C,
608 13
620 13 S620G, S620I,
593 13 I593K, I593T, I593X, I593R, I593V,
626 13 G626V, G626A, G626S,
588 13 N588K, N588K, N588D,
562 13 H562P, H562Q, H562Q, H562R,
624 13 S624R, S624N, S624R, S624R,
644 14 V644F, V644I,
641 14 S641P, S641F,
558 14 A558P, A558V, A558E,
586 14 L586M,
566 14 C566F, C566S, C566R, C566S, C566G,
625 14 V625E,
640 14 F640Del, F640L, F640L, F640L, F640V,
569 14 Y569X, Y569C, Y569H,
584 14 G584S, G584C, G584R,
557 14
628 14 G628Del, G628D, G628V, G628R, G628S, G628A,
618 14 T618S, T618S,
585 14 W585C, W585C,
622 14 L622F,
648 15 G648A,
629 15 N629K, N629I, N629T, N629S, N629K, N629D,
637 15 E637X, E637K, E637G,
649 15
606 15 S606F, S606Del, S606P,
627 15 F627L, F627L, F627fsX, F627X, F627L,
571 15 I571L, I571V,
647 15