KCNQ1 Variant K598R Detail

We estimate the penetrance of LQTS for KCNQ1 K598R is 78%. This variant was found in a total of 2 carriers in 3 papers or gnomAD, 2 had LQTS. K598R is not present in gnomAD. K598R has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K598R around 78% (9/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.0 0.771 1 0.744 83
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 LQT1 Other Disease
32893267 2020 2 None 2 None
30758498 2019 1 None None None
18596570 2008 1 None None None
LITERATURE, COHORT, AND GNOMAD: - 2 0 2
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.

K598R 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. This results from the fact that the functional KV7.1 channel 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
598 0 K598R,
597 4
599 4
596 5 E596del, E596K,
600 5 T600M,
595 7 V595L, V595L,
601 7
594 8 R594Q, R594P,
602 8
593 8 N593S,
603 8
592 9
604 9
591 10 R591H, R591C, R591L,
605 10
590 11 A590T,
606 11
589 11 G589D, G589S,
607 11 A607T,
588 12 I588F,
608 12
587 13 T587M, T587R,
609 13
586 13 N586D,
610 13
585 14 S585N,
611 14 D611N, D611Y,
584 14 G584S,
612 14
583 15 R583H, R583C, R583G,
613 15