KCNH2 Variant G584V Detail

We estimate the penetrance of LQTS for KCNH2 G584V is 57%. We are unaware of any observations of this variant in individuals. G584V is not present in gnomAD. G584V 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 G584V around 57% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.522 0.999 -3 0.936 58
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.

G584V has 56 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
584 0 G584R, G584C, G584S,
583 4 I583V,
587 5
633 6 N633I, N633D, N633S,
588 6 N588D, N588K, N588K,
585 6 W585C, W585C,
586 6 L586M,
634 6 T634A, T634S, T634S, T634P, T634I,
637 7 E637G, E637X, E637K,
572 8 G572C, G572S, G572D, G572R,
631 8 S631F,
632 8 P632S, P632A,
589 9 L589P,
576 9
593 9 I593V, I593K, I593X, I593T, I593R,
592 10 Q592X,
575 10 E575K,
577 10
571 10 I571L, I571V,
630 10 V630A, V630I, V630T,
590 10 G590D, G590V,
568 10 W568C, W568C,
636 10
591 10 D591N, D591H,
635 11 N635I,
638 11 K638R, K638Del, K638E, K638D,
629 11 N629T, N629K, N629D, N629S, N629K, N629I,
573 11
597 11 Y597H, Y597C,
592 11 Q592X,
594 12
569 12 Y569H, Y569C, Y569X,
570 13
613 13 T613L, T613M, T613A, T613K,
617 13 F617V, F617L, F617L, F617L,
610 13
629 13 N629T, N629K, N629D, N629S, N629K, N629I,
628 13 G628R, G628Del, G628S, G628V, G628D, G628A,
589 13 L589P,
605 13 P605L,
614 13 A614T, A614V,
596 13 P596L, P596R, P596T, P596S,
640 14 F640L, F640L, F640V, F640Del, F640L,
591 14 D591N, D591H,
574 14 M574V, M574L, M574L,
595 14 K595N, K595N, K595E,
590 14 G590D, G590V,
593 14 I593V, I593K, I593X, I593T, I593R,
628 14 G628R, G628Del, G628S, G628V, G628D, G628A,
641 14 S641P, S641F,
616 14 Y616S,
627 14 F627L, F627fsX, F627L, F627X, F627L,
639 14 I639F, I639N,
609 15 D609G, D609N,
613 15 T613L, T613M, T613A, T613K,
604 15 G604S, G604D, G604C,