KCNH2 Variant A430V Detail

We estimate the penetrance of LQTS for KCNH2 A430V is 51%. We are unaware of any observations of this variant in individuals. A430V is not present in gnomAD. A430V 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A430V around 51% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.673 0.243 0 0.9 60
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 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.

A430V has 52 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
430 0
429 4 A429V, A429P,
431 4 F431L, F431L, F431L,
432 6
428 6 S428fsX, S428X, S428L,
566 6 C566R, C566G, C566F, C566S, C566S,
569 6 Y569C, Y569X, Y569H,
426 6 P426H,
427 7 Y427H, Y427S, Y427C,
570 7
573 9
567 9 I567T, I567M,
425 9
522 9 G522E,
565 9
523 9
574 10 M574L, M574L, M574V,
611 10 Y611D,
610 10
607 10
562 11 H562P, H562Q, H562R, H562Q,
526 11
572 11 G572C, G572D, G572R, G572S,
571 11 I571L, I571V,
525 11 K525N, K525N,
424 11
563 11 W563X, W563G, W563C, W563C,
423 12
568 12 W568C, W568C,
614 12 A614T, A614V,
520 12
564 12 L564L,
422 13 A422T,
524 13
521 13
529 14
586 14 L586M,
615 14 L615V, L615F,
528 14 R528P, R528W, R528X,
609 14 D609N, D609G,
585 14 W585C, W585C,
561 14 A561P, A561T, A561V,
612 14 V612A, V612L, V612L,
606 14 S606P, S606Del, S606F,
421 14 T421fsX, T421M,
613 14 T613K, T613M, T613L, T613A,
608 14
575 15 E575K,
527 15
452 15
576 15
605 15 P605L,