KCNQ1 Variant G643S Detail

We estimate the penetrance of LQTS for KCNQ1 G643S is 0%. This variant was found in a total of 1559 carriers in 19 papers or gnomAD, 3 had LQTS. G643S is present in 1433 alleles in gnomAD. G643S has been functionally characterized in 1 papers. 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G643S around 0% (4/1569).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
2
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
33552729 2021 1 1 0 DCM
32145446 2020 1 None None None
31751991 2020 3 None None Acute MI
29855564 2018 7 None None None
29197658 2018 11 None 11 None
27325960 2010 2 2 None Lone AF
26385840 2015 1 None None None
26118593 2015 1 None 1 None
24573873 2007 3 1 2 None
24363352 2014 8 None None None
24284363 2014 6 6 None 6 sudden death w/ psychotropic drugs, perhaps not SCD
23714088 2013 1 None None None
22949429 2012 32 32 None None
21139297 2010 1 1 None TdP after MI - AF history
19841300 2009 32 32 None None
17016049 2007 140 140 None atrial fibrillation
16723781 2006 88 81 0 None
15028050 2004 5 None 5 None
11761407 2001 12 7 5 None
LITERATURE, COHORT, AND GNOMAD: - 1559 1556 3
VARIANT FEATURES ALONE: - 10 9 1 -
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)
11761407 COS 35 1.1 1.0 0.72

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)
11761407 COS 71 0.0 1.0 0.76

G643S 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
643 0 G643S,
642 4
644 4
641 5 P641L,
645 5
640 7 Q640L,
646 7
639 8
647 8
638 8
648 8 V648I,
637 9
649 9 D649N, D649G,
636 10
650 10
635 11 G635R, G635R,
651 11
634 11
652 11
633 12
653 12 F653Y,
632 13
654 13
631 13 P631R,
655 13
630 14 P630S, P630T,
656 14
629 14 G629S,
657 14 N657S,
628 15 G628S, G628D,
658 15 T658N,