KCNQ1 Variant W379R Detail

We estimate the penetrance of LQTS for KCNQ1 W379R is 84%. This variant was found in a total of 2 carriers in 4 papers or gnomAD, 2 had LQTS. W379R is not present in gnomAD. W379R has been functionally characterized in 1 papers. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 W379R around 84% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-13.48 1.0 1 0.889 92
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 2 None 2 None
26066609 2015 1 None 1 None
22677073 2012 1 None None SUDS
17222736 2007 1 None None 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)
26066609 Oocytes 0 None 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)
26066609 Oocytes 25 12.0 None None

W379R has 32 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
379 0 W379R, W379R, W379C, W379C, W379G,
383 5
382 6
378 6 A378T,
380 6 R380S, R380S, R380G,
391 7 T391A, T391I,
381 7 C381Y,
376 8
377 8
375 8
384 9
389 9 S389P,
390 9
518 9 R518Q, R518G,
386 10 N386K, N386K,
385 11 E385K,
392 11 W392R, W392R, W392ins,
374 11 L374H, L374F,
522 11 Y522S,
373 12 S373P,
372 12
387 13 P387T,
521 13
515 13
393 13 K393N,
388 13 D388H, D388N,
519 14 R519H, R519C,
514 14 I514T,
371 14 A371T,
525 14 A525T, A525V,
394 15 I394L,
517 15 I517T,