KCNQ1 Variant Y522S Detail

We estimate the penetrance of LQTS for KCNQ1 Y522S is 73%. This variant was found in a total of 6 carriers in 2 papers or gnomAD, 6 had LQTS. Y522S is not present in gnomAD. Y522S 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y522S around 73% (11/16).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.76 0.771 2 0.919 65
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
26066609 2015 5 None 5 None
19716085 2009 1 None 1 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 10 7.0 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)
26066609 Oocytes 60 0.0 None 0.6

Y522S has 35 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
522 0 Y522S,
523 5
377 5
378 6 A378T,
374 6 L374H, L374F,
526 6 K526Q, K526E,
525 6 A525T, A525V,
381 7 C381Y,
519 7 R519H, R519C,
521 7
524 7 V524G,
373 8 S373P,
380 9 R380S, R380S, R380G,
375 9
520 9 M520R,
518 9 R518Q, R518G,
376 10
527 10
529 10
528 10
371 11 A371T,
372 11
530 11
517 11 I517T,
370 11 A370V,
516 11
379 11 W379R, W379R, W379C, W379C, W379G,
515 11
382 12
384 12
383 12
385 14 E385K,
514 14 I514T,
369 14
531 15