KCNH2 Variant A558V Detail

We estimate the penetrance of LQTS for KCNH2 A558V is 45%. This variant was found in a total of 3 carriers in 0 papers or gnomAD, 0 had LQTS. A558V is present in 3 alleles in gnomAD. A558V 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A558V around 45% (5/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.467 0.574 0 0.86 67
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: - 3 3 0 -
VARIANT FEATURES ALONE: - 10 5 5 -
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)
19892732 Xeno -29.5 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)
19892732 Xeno None None None

A558V has 64 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
558 0 A558V, A558E, A558P,
559 4 L559F, L559H,
557 5
561 5 A561P, A561T, A561V,
560 5 I560fsX, I560M,
556 6
555 6
562 6 H562P, H562Q, H562R, H562Q,
619 7
554 7
563 8 W563X, W563G, W563C, W563C,
615 8 L615V, L615F,
646 8
423 9
618 9 T618S, T618S,
564 10 L564L,
422 10 A422T,
622 10 L622F,
419 10
642 10 I642V, I642Del,
553 10 L553V,
565 10
552 11 L552S,
551 11 F551L, F551L, F551L,
651 11 M651K,
655 11
611 11 Y611D,
645 11 M645R, M645L, M645L, M645I, M645V, M645I, M645I,
566 12 C566R, C566G, C566F, C566S, C566S,
623 12 T623I,
649 12
643 12
656 12 F656L, F656L, F656L,
614 12 A614T, A614V,
426 13 P426H,
620 13 S620I, S620G,
648 13 G648A,
550 13
652 13 Y652X,
424 13
612 13 V612A, V612L, V612L,
647 13
621 13 S621R, S621N, S621R, S621R,
650 13 L650X,
647 13
644 13 V644F, V644I,
639 13 I639F, I639N,
421 14 T421fsX, T421M,
418 14
617 14 F617L, F617L, F617V, F617L,
532 14
567 14 I567T, I567M,
616 14 Y616S,
427 14 Y427H, Y427S, Y427C,
641 14 S641P, S641F,
648 14 G648A,
644 14 V644F, V644I,
415 14
420 14 Y420C,
425 14
416 15
529 15
659 15
654 15