KCNQ1 Variant C642S Detail

We estimate the penetrance of LQTS for KCNQ1 C642S is 10%. We are unaware of any observations of this variant in individuals. C642S is not present in gnomAD. C642S has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT1 and 10 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C642S around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.02 0.0 0 0.545 1
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 10 0 -
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.

C642S 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
642 0
641 4 P641L,
643 4 G643S,
640 5 Q640L,
644 5
639 7
645 7
638 8
646 8
637 8
647 8
636 9
648 9 V648I,
635 10 G635R, G635R,
649 10 D649N, D649G,
634 11
650 11
633 11
651 11
632 12
652 12
631 13 P631R,
653 13 F653Y,
630 13 P630S, P630T,
654 13
629 14 G629S,
655 14
628 14 G628S, G628D,
656 14
627 15
657 15 N657S,