KCNH2 Variant G572A Detail

We estimate the penetrance of LQTS for KCNH2 G572A is 78%. We are unaware of any observations of this variant in individuals. G572A is not present in gnomAD. G572A 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G572A around 78% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.607 0.944 0 0.922 88
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 3 7 -
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.

G572A has 51 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
572 0 G572C, G572S, G572D, G572R,
573 4
571 4 I571L, I571V,
570 5
575 6 E575K,
569 6 Y569H, Y569C, Y569X,
586 6 L586M,
576 6
585 6 W585C, W585C,
574 6 M574V, M574L, M574L,
568 7 W568C, W568C,
584 8 G584R, G584C, G584S,
637 8 E637G, E637X, E637K,
636 9
587 9
634 9 T634A, T634S, T634S, T634P, T634I,
577 10
567 10 I567T, I567M,
610 10
583 10 I583V,
430 11
431 11 F431L, F431L, F431L,
566 11 C566S, C566F, C566G, C566R, C566S,
614 11 A614T, A614V,
565 11
640 11 F640L, F640L, F640V, F640Del, F640L,
589 12 L589P,
633 12 N633I, N633D, N633S,
588 12 N588D, N588K, N588K,
597 12 Y597H, Y597C,
632 12 P632S, P632A,
613 12 T613L, T613M, T613A, T613K,
635 12 N635I,
605 12 P605L,
631 13 S631F,
617 13 F617V, F617L, F617L, F617L,
630 13 V630A, V630I, V630T,
638 13 K638R, K638Del, K638E, K638D,
590 13 G590D, G590V,
607 14
639 14 I639F, I639N,
564 14 L564L,
609 14 D609G, D609N,
604 14 G604S, G604D, G604C,
429 14 A429V, A429P,
611 14 Y611D,
432 14
641 14 S641P, S641F,
606 15 S606P, S606F, S606Del,
618 15 T618S, T618S,
603 15 G603D,