KCNQ1 Variant R397Q Detail

We estimate the penetrance of LQTS for KCNQ1 R397Q is 16%. This variant was found in a total of 6 carriers in 2 papers or gnomAD, 1 had LQTS. R397Q is present in 4 alleles in gnomAD. R397Q 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R397Q around 16% (2/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.81 0.963 1 0.633 16
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
25616976 2015 1 None 1 DCM w/ VT
24440382 2014 1 None None Fibrosis + SUDS
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)
25616976 HEK 90 0.0 None None

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)
25616976 HEK None None None

R397Q 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
397 0 R397W, R397Q, R397G,
396 4
398 4 K398R,
395 5 Y395C,
399 5 A399S, A399V, A399G,
394 7 I394L,
400 7
393 8 K393N,
401 8 R401W, R401Q,
392 8 W392R, W392R, W392ins,
402 8
391 9 T391A, T391I,
403 9 H403P,
390 10
404 10
389 11 S389P,
405 11
388 11 D388H, D388N,
406 11
387 12 P387T,
407 12
386 13 N386K, N386K,
408 13 P408A,
385 13 E385K,
409 13
384 14
410 14
383 14
411 14
382 15
412 15 P412S,