KCNQ1 Variant R452L Detail

We estimate the penetrance of LQTS for KCNQ1 R452L is 12%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. R452L is present in 2 alleles in gnomAD. R452L 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 R452L around 12% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.03 0.016 0 0.6 8
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 65 4.9 1.73 1.02

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 64 0.94 2.23 0.98

R452L 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
452 0 R452Q, R452W, R452L,
451 4 R451Q, R451W,
453 4
450 5 E450K,
454 5
449 7 E449K,
455 7 H455Y, H455Q, H455Q, H455R,
448 8 P448R, P448Q, P448L, P448S,
456 8 F456L, F456L, F456L,
447 8 P447H,
457 8
446 9 D446E, D446E, D446E, D446E, D446N,
458 9
445 10
459 10 D459N, D459V,
444 11 T444M, T444K,
460 11 G460S, G460D, G460C,
443 11
461 11
442 12 H442R,
462 12
441 13 P441S,
463 13 S463T,
440 13
464 13 S464P,
439 14
465 14
438 14
466 14
437 15 M437V,
467 15 K467R,