KCNH2 Variant D609Y Detail

We estimate the penetrance of LQTS for KCNH2 D609Y is 85%. We are unaware of any observations of this variant in individuals. D609Y is not present in gnomAD. D609Y 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 D609Y around 85% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.069 0.984 -3 0.873 90
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.

D609Y has 57 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
609 0 D609N, D609G,
610 5
606 5 S606Del, S606P, S606F,
608 5
612 5 V612L, V612A, V612L,
635 6 N635I,
613 6 T613M, T613A, T613K, T613L,
607 6
611 7 Y611D,
605 7 P605L,
638 8 K638E, K638D, K638Del, K638R,
614 8 A614V, A614T,
589 8 L589P,
593 9 I593R, I593V, I593X, I593T, I593K,
634 9 T634P, T634I, T634S, T634A, T634S,
595 10 K595N, K595N, K595E,
615 10 L615F, L615V,
586 10 L586M,
569 10 Y569H, Y569X, Y569C,
431 10 F431L, F431L, F431L,
639 10 I639F, I639N,
616 10 Y616S,
604 10 G604C, G604S, G604D,
636 10
633 10 N633D, N633I, N633S,
585 11 W585C, W585C,
590 11 G590V, G590D,
592 11 Q592X,
565 12
594 12
427 12 Y427C, Y427H, Y427S,
637 12 E637G, E637X, E637K,
632 12 P632A, P632S,
630 12 V630A, V630I, V630T,
568 13 W568C, W568C,
566 13 C566S, C566R, C566G, C566F, C566S,
617 13 F617L, F617V, F617L, F617L,
629 13 N629T, N629K, N629D, N629I, N629K, N629S,
642 13 I642V, I642Del,
588 13 N588K, N588K, N588D,
603 13 G603D,
562 14 H562Q, H562Q, H562R, H562P,
573 14
597 14 Y597H, Y597C,
430 14
641 14 S641P, S641F,
596 14 P596S, P596L, P596T, P596R,
591 14 D591H, D591N,
583 14 I583V,
572 14 G572D, G572R, G572C, G572S,
618 14 T618S, T618S,
587 14
584 15 G584S, G584R, G584C,
570 15
432 15
575 15 E575K,
619 15