KCNH2 Variant S606T Detail

We estimate the penetrance of LQTS for KCNH2 S606T is 68%. We are unaware of any observations of this variant in individuals. S606T is not present in gnomAD. S606T 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S606T around 68% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.367 0.616 2 0.79 81
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 4 6 -
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.

S606T has 43 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
606 0 S606P, S606F, S606Del,
605 4 P605L,
607 4
609 5 D609N, D609G,
610 5
608 6
604 7 G604S, G604D, G604C,
595 7 K595N, K595E, K595N,
635 9 N635I,
593 9 I593X, I593V, I593R, I593K, I593T,
612 9 V612L, V612A, V612L,
589 9 L589P,
603 10 G603D,
613 10 T613A, T613L, T613K, T613M,
594 10
611 10 Y611D,
431 10 F431L, F431L, F431L,
586 11 L586M,
590 11 G590D, G590V,
569 11 Y569H, Y569C, Y569X,
597 11 Y597H, Y597C,
634 12 T634S, T634I, T634S, T634P, T634A,
596 12 P596L, P596S, P596T, P596R,
614 12 A614T, A614V,
638 12 K638Del, K638E, K638D, K638R,
427 12 Y427C, Y427H, Y427S,
585 13 W585C, W585C,
592 13 Q592X,
633 13 N633D, N633I, N633S,
432 13
636 13
573 14
587 14
591 14 D591N, D591H,
639 14 I639F, I639N,
430 14
615 14 L615V, L615F,
588 14 N588K, N588K, N588D,
572 15 G572S, G572R, G572C, G572D,
583 15 I583V,
565 15
616 15 Y616S,
566 15 C566G, C566S, C566R, C566F, C566S,