KCNH2 Variant A614P Detail

We estimate the penetrance of LQTS for KCNH2 A614P is 80%. We are unaware of any observations of this variant in individuals. A614P is not present in gnomAD. A614P 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 A614P around 80% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.738 1.0 -1 0.949 87
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.

A614P has 80 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
614 0 A614T, A614V,
613 4 T613L, T613M, T613A, T613K,
615 4 L615F, L615V,
565 5
612 6 V612A, V612L, V612L,
617 6 F617V, F617L, F617L, F617L,
611 6 Y611D,
568 6 W568C, W568C,
618 6 T618S, T618S,
616 7 Y616S,
566 8 C566S, C566F, C566G, C566R, C566S,
585 8 W585C, W585C,
610 8
569 8 Y569H, Y569C, Y569X,
609 8 D609G, D609N,
630 8 V630A, V630I, V630T,
564 8 L564L,
561 9 A561V, A561T, A561P,
638 9 K638R, K638Del, K638E, K638D,
619 9
562 9 H562R, H562Q, H562Q, H562P,
567 9 I567T, I567M,
620 10 S620G, S620I,
642 10 I642V, I642Del,
586 10 L586M,
431 10 F431L, F431L, F431L,
589 10 L589P,
570 10
621 11 S621R, S621R, S621R, S621N,
640 11 F640L, F640L, F640V, F640Del, F640L,
571 11 I571L, I571V,
607 11
631 11 S631F,
608 11
635 11 N635I,
639 11 I639F, I639N,
572 11 G572C, G572S, G572D, G572R,
629 11 N629T, N629K, N629D, N629S, N629K, N629I,
637 12 E637G, E637X, E637K,
427 12 Y427H, Y427C, Y427S,
622 12 L622F,
641 12 S641P, S641F,
430 12
632 12 P632S, P632A,
606 12 S606P, S606F, S606Del,
644 12 V644I, V644F,
632 12 P632S, P632A,
627 12 F627L, F627fsX, F627L, F627X, F627L,
558 12 A558E, A558V, A558P,
563 12 W563C, W563X, W563G, W563C,
641 12 S641P, S641F,
573 12
645 12 M645I, M645R, M645I, M645L, M645L, M645V, M645I,
628 13 G628R, G628Del, G628S, G628V, G628D, G628A,
560 13 I560fsX, I560M,
605 13 P605L,
588 13 N588D, N588K, N588K,
633 13 N633I, N633D, N633S,
426 13 P426H,
626 13 G626S, G626A, G626V,
634 13 T634A, T634S, T634S, T634P, T634I,
592 13 Q592X,
584 13 G584R, G584C, G584S,
559 14 L559H, L559F,
623 14 T623I,
627 14 F627L, F627fsX, F627L, F627X, F627L,
593 14 I593V, I593K, I593X, I593T, I593R,
625 14 V625E,
423 14
636 14
637 14 E637G, E637X, E637K,
557 14
590 14 G590D, G590V,
636 15
631 15 S631F,
633 15 N633I, N633D, N633S,
587 15
429 15 A429V, A429P,
646 15
643 15