KCNQ1 Variant P441S Detail

We estimate the penetrance of LQTS for KCNQ1 P441S is 8%. This variant was found in a total of 8 carriers in 2 papers or gnomAD, 0 had LQTS. P441S is present in 7 alleles in gnomAD. P441S 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 P441S around 8% (1/18).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.03 0.985 -1 0.643 3
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
22949429 2012 1 1 None None
19841300 2009 1 1 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)
34930020 HEK 39 -0.41 1.03 0.99

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 85 1.49 1.38 0.98

P441S 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
441 0 P441S,
440 4
442 4 H442R,
439 5
443 5
438 7
444 7 T444M, T444K,
437 8 M437V,
445 8
436 8
446 8 D446E, D446E, D446E, D446E, D446N,
435 9
447 9 P447H,
434 10 G434R, G434R,
448 10 P448R, P448Q, P448L, P448S,
433 11 P433A,
449 11 E449K,
432 11 T432I, T432A,
450 11 E450K,
431 12 V431L, V431L,
451 12 R451Q, R451W,
430 13
452 13 R452Q, R452W, R452L,
429 13 N429S,
453 13
428 14 D428G,
454 14
427 14
455 14 H455Y, H455Q, H455Q, H455R,
426 15
456 15 F456L, F456L, F456L,