KCNQ1 Variant R555C Detail

We estimate the penetrance of LQTS for KCNQ1 R555C is 45%. This variant was found in a total of 9 carriers in 12 papers or gnomAD, 5 had LQTS. R555C is present in 2 alleles in gnomAD. R555C has been functionally characterized in 4 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R555C around 45% (8/19).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.01 1.0 -4 0.93 39
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 5 None 5 None
30758498 2019 6 None 1 None
26715165 2016 2 None 2 None
24363352 2014 1 None None None
23631430 2013 3 None None None
23631430 2013 1 None None None
19934648 2010 None None None None
19716085 2009 4 None 4 None
19261104 2008 2 2 None None
17192539 2006 4 None 4 None
15746441 2005 None None None None
12877697 2003 1 1 None None
LITERATURE, COHORT, AND GNOMAD: - 9 4 5
VARIANT FEATURES ALONE: - 10 7 3 -
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)
22456477 HEK None None None
9312006 COS 25 60.0 None None
19934648 Oocytes 8 35.0 1.0 None
25037568 CHO 12 68.0 1.494505495 0.634074074

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)
22456477 HEK 60 None None None
9312006 COS 40 30.0 1.0 0.487698987
19934648 Oocytes None None None
25037568 CHO None None None

R555C has 15 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
555 7 R555H, R555C, R555S, R555L,
556 8
552 9 L552F,
554 9
553 9
559 10 L559P,
557 10 K557E,
558 10
560 11
551 11
549 12
550 12
548 13 G548S,
563 14
561 15