KCNH2 Variant R582G Detail

We estimate the penetrance of LQTS for KCNH2 R582G is 47%. We are unaware of any observations of this variant in individuals. R582G is not present in gnomAD. R582G 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R582G around 47% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.455 0.005 -1 0.698 53
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 6 4 -
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.

R582G has 31 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
582 0 R582H, R582C, R582L, R582P,
581 4
583 4 I583V,
580 5 D580Y,
584 5 G584S, G584C, G584R,
579 7 M579V, M579I, M579T, M579I, M579I,
585 7 W585C, W585C,
578 8
586 8 L586M,
577 8
587 8
576 9
588 9 N588K, N588D, N588K,
575 10 E575K,
589 10 L589P,
574 11 M574V, M574L, M574L,
590 11 G590D, G590V,
573 11
591 11 D591N, D591H,
572 12 G572D, G572R, G572C, G572S,
592 12 Q592X,
571 13 I571V, I571L,
593 13 I593R, I593K, I593V, I593T, I593X,
570 13
594 13
569 14 Y569H, Y569C, Y569X,
595 14 K595E, K595N, K595N,
568 14 W568C, W568C,
596 14 P596S, P596R, P596L, P596T,
567 15 I567M, I567T,
597 15 Y597H, Y597C,