KCNH2 Variant S600T Detail

We estimate the penetrance of LQTS for KCNH2 S600T is 52%. We are unaware of any observations of this variant in individuals. S600T is not present in gnomAD. S600T 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 S600T around 52% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.203 0.034 2 0.628 65
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.

S600T 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
600 0
599 4 S599N,
601 4 G601S,
598 5
602 5 L602X,
597 7 Y597C, Y597H,
603 7 G603D,
596 8 P596T, P596L, P596S, P596R,
604 8 G604C, G604D, G604S,
595 8 K595N, K595N, K595E,
605 8 P605L,
594 9
606 9 S606Del, S606P, S606F,
593 10 I593R, I593V, I593T, I593X, I593K,
607 10
592 11 Q592X,
608 11
591 11 D591H, D591N,
609 11 D609N, D609G,
590 12 G590V, G590D,
610 12
589 13 L589P,
611 13 Y611D,
588 13 N588K, N588K, N588D,
612 13 V612L, V612A, V612L,
587 14
613 14 T613A, T613K, T613M, T613L,
586 14 L586M,
614 14 A614V, A614T,
585 15 W585C, W585C,
615 15 L615V, L615F,