KCNH2 Variant Q592R Detail

We estimate the penetrance of LQTS for KCNH2 Q592R is 57%. We are unaware of any observations of this variant in individuals. Q592R is not present in gnomAD. Q592R 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 Q592R around 57% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.244 0.941 1 0.78 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: - 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.

Q592R 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
592 0 Q592X,
593 5 I593X, I593V, I593R, I593K, I593T,
589 5 L589P,
591 5 D591N, D591H,
588 6 N588K, N588K, N588D,
590 6 G590D, G590V,
633 6 N633D, N633I, N633S,
629 7 N629K, N629S, N629K, N629I, N629D, N629T,
594 8
630 9 V630I, V630T, V630A,
583 9 I583V,
595 9 K595N, K595E, K595N,
584 10 G584C, G584S, G584R,
632 10 P632S, P632A,
634 10 T634S, T634I, T634S, T634P, T634A,
631 10 S631F,
628 10 G628V, G628R, G628A, G628D, G628Del, G628S,
613 10 T613A, T613L, T613K, T613M,
586 10 L586M,
585 10 W585C, W585C,
588 11 N588K, N588K, N588D,
596 11 P596L, P596S, P596T, P596R,
587 11
638 11 K638Del, K638E, K638D, K638R,
631 11 S631F,
605 11 P605L,
609 11 D609N, D609G,
584 11 G584C, G584S, G584R,
635 12 N635I,
616 12 Y616S,
637 12 E637G, E637X, E637K,
610 12
597 13 Y597H, Y597C,
604 13 G604S, G604D, G604C,
606 13 S606P, S606F, S606Del,
628 13 G628V, G628R, G628A, G628D, G628Del, G628S,
627 13 F627X, F627L, F627fsX, F627L, F627L,
612 13 V612L, V612A, V612L,
630 13 V630I, V630T, V630A,
587 13
614 13 A614T, A614V,
633 14 N633D, N633I, N633S,
585 14 W585C, W585C,
617 14 F617V, F617L, F617L, F617L,
629 14 N629K, N629S, N629K, N629I, N629D, N629T,
583 14 I583V,
591 14 D591N, D591H,
632 14 P632S, P632A,
636 14
628 14 G628V, G628R, G628A, G628D, G628Del, G628S,
629 15 N629K, N629S, N629K, N629I, N629D, N629T,
568 15 W568C, W568C,