KCNQ1 Variant G626S Detail

We estimate the penetrance of LQTS for KCNQ1 G626S is 36%. This variant was found in a total of 5 carriers in 3 papers or gnomAD, 3 had LQTS. G626S is present in 2 alleles in gnomAD. G626S has been functionally characterized in 1 papers. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G626S around 36% (5/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.07 0.079 0 0.566 35
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
19716085 2009 1 None 1 None
19322600 2009 2 None 1 None
16922724 2006 1 None 1 None
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
34930020 HEK 89 0.44 0.99 1.07

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
34930020 HEK 115 3.73 1.55 0.96

G626S 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
626 0 G626S,
625 4 P625R,
627 4
624 5
628 5 G628S, G628D,
623 7
629 7 G629S,
622 8 G622S,
630 8 P630S, P630T,
621 8 G621S, G621C, G621D,
631 8 P631R,
620 9
632 9
619 10 L619M,
633 10
618 11
634 11
617 11
635 11 G635R, G635R,
616 12
636 12
615 13
637 13
614 13 H614del,
638 13
613 14
639 14
612 14
640 14 Q640L,
611 15 D611N, D611Y,
641 15 P641L,