KCNQ1 Variant C381W Detail

We estimate the penetrance of LQTS for KCNQ1 C381W is 26%. We are unaware of any observations of this variant in individuals. C381W is not present in gnomAD. C381W 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 C381W around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.95 0.999 -2 0.798 30
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
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 73 6.22 1.92 0.75

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 104 2.44 1.28 0.93

C381W has 37 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
381 0 C381Y,
378 5 A378T,
518 5 R518Q, R518G,
384 6
377 6
383 6
380 6 R380S, R380S, R380G,
519 7 R519H, R519C,
522 7 Y522S,
382 7
515 7
379 7 W379R, W379R, W379C, W379C, W379G,
385 8 E385K,
521 9
523 9
516 9
517 10 I517T,
391 10 T391A, T391I,
514 10 I514T,
374 10 L374H, L374F,
376 10
392 10 W392R, W392R, W392ins,
520 11 M520R,
375 11
386 11 N386K, N386K,
525 12 A525T, A525V,
389 12 S389P,
373 12 S373P,
512 12
526 12 K526Q, K526E,
387 12 P387T,
524 13 V524G,
513 13 T513A, T513S, T513S,
511 13 R511Q, R511W,
390 14
372 14
371 15 A371T,