KCNH2 Variant A561G Detail

We estimate the penetrance of LQTS for KCNH2 A561G is 69%. We are unaware of any observations of this variant in individuals. A561G is not present in gnomAD. A561G has been functionally characterized in 1 papers. 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A561G around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.834 0.998 0 0.899 77
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 4 6 -
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
19892735 Xeno -28.1 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
19892735 Xeno None None None

A561G has 69 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
561 0 A561P, A561V, A561T,
560 4 I560M, I560fsX,
564 5 L564L,
558 5 A558V, A558P, A558E,
562 5 H562Q, H562R, H562P, H562Q,
618 5 T618S, T618S,
619 6
565 6
615 6 L615V, L615F,
559 6 L559F, L559H,
563 6 W563C, W563C, W563G, W563X,
557 7
622 7 L622F,
566 8 C566G, C566F, C566R, C566S, C566S,
614 9 A614V, A614T,
556 9
567 9 I567T, I567M,
644 9 V644F, V644I,
617 9 F617L, F617L, F617V, F617L,
611 9 Y611D,
621 10 S621R, S621R, S621N, S621R,
620 10 S620I, S620G,
642 10 I642Del, I642V,
423 10
623 10 T623I,
647 10
555 11
651 11 M651K,
568 11 W568C, W568C,
648 11 G648A,
646 11
422 11 A422T,
640 11 F640L, F640L, F640V, F640Del, F640L,
426 11 P426H,
616 11 Y616S,
645 11 M645L, M645I, M645R, M645L, M645I, M645V, M645I,
612 11 V612L, V612L, V612A,
554 12
613 12 T613K, T613L, T613M, T613A,
643 12
427 13 Y427C, Y427H, Y427S,
641 13 S641P, S641F,
655 13
652 13 Y652X,
419 13
569 13 Y569H, Y569X, Y569C,
649 13
645 14 M645L, M645I, M645R, M645L, M645I, M645V, M645I,
641 14 S641P, S641F,
553 14 L553V,
639 14 I639F, I639N,
431 14 F431L, F431L, F431L,
624 14 S624R, S624R, S624N, S624R,
643 14
570 14
656 14 F656L, F656L, F656L,
424 14
425 14
430 14
638 14 K638R, K638D, K638E, K638Del,
649 14
625 14 V625E,
529 14
650 14 L650X,
571 15 I571V, I571L,
630 15 V630T, V630I, V630A,
646 15
552 15 L552S,
421 15 T421M, T421fsX,