KCNH2 Variant Y611S Detail

We estimate the penetrance of LQTS for KCNH2 Y611S is 78%. We are unaware of any observations of this variant in individuals. Y611S is not present in gnomAD. Y611S 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y611S around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.536 0.999 -2 0.971 83
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 3 7 -
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.

Y611S 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
611 0 Y611D,
612 5 V612A, V612L, V612L,
615 6 L615F, L615V,
614 6 A614T, A614V,
565 6
427 7 Y427C, Y427S, Y427H,
562 7 H562P, H562Q, H562Q, H562R,
609 7 D609G, D609N,
608 7
566 7 C566F, C566S, C566R, C566S, C566G,
431 7 F431L, F431L, F431L,
613 7 T613K, T613M, T613L, T613A,
610 7
607 8
569 9 Y569X, Y569C, Y569H,
561 9 A561V, A561T, A561P,
639 10 I639N, I639F,
635 10 N635I,
423 10
430 10
426 10 P426H,
638 10 K638E, K638R, K638D, K638Del,
618 10 T618S, T618S,
606 10 S606F, S606Del, S606P,
616 10 Y616S,
642 11 I642V, I642Del,
568 11 W568C, W568C,
564 11 L564L,
424 11
619 11
617 11 F617L, F617L, F617V, F617L,
558 11 A558P, A558V, A558E,
567 11 I567T, I567M,
428 11 S428X, S428L, S428fsX,
563 12 W563G, W563X, W563C, W563C,
559 12 L559H, L559F,
585 12 W585C, W585C,
570 12
429 12 A429P, A429V,
432 13
605 13 P605L,
586 13 L586M,
422 13 A422T,
425 13
589 13 L589P,
636 13
560 13 I560M, I560fsX,
641 14 S641P, S641F,
630 14 V630I, V630A, V630T,
573 14
634 14 T634P, T634S, T634I, T634S, T634A,
620 14 S620G, S620I,
572 14 G572S, G572C, G572R, G572D,
571 14 I571L, I571V,
645 15 M645L, M645I, M645I, M645R, M645L, M645V, M645I,
643 15
632 15 P632S, P632A,
557 15