KCNQ1 Variant T513S Detail

We estimate the penetrance of LQTS for KCNQ1 T513S is 14%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 0 had LQTS. T513S is present in 1 alleles in gnomAD. T513S has not been functionally characterized. 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T513S around 14% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.06 0.027 1 0.62 14
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
23631430 2013 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.

T513S has 24 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
513 0 T513A, T513S, T513S,
512 4
514 4 I514T,
516 6
510 6 H510R, H510Y,
517 6 I517T,
509 7 H509Q, H509Q, H509R,
515 7
511 8 R511Q, R511W,
518 9 R518Q, R518G,
508 10 E508G,
520 10 M520R,
519 11 R519H, R519C,
392 11 W392R, W392R, W392ins,
384 11
521 12
381 13 C381Y,
394 13 I394L,
380 14 R380S, R380S, R380G,
385 14 E385K,
387 14 P387T,
391 14 T391A, T391I,
383 14
523 15