KCNQ1 Variant P387T Detail

We estimate the penetrance of LQTS for KCNQ1 P387T is 19%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. P387T is present in 1 alleles in gnomAD. P387T 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 P387T around 19% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.44 0.006 -1 0.619 22
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
LITERATURE, COHORT, AND GNOMAD: - 1 1 0
VARIANT FEATURES ALONE: - 10 8 2 -
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.

P387T has 25 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
387 0 P387T,
386 4 N386K, N386K,
388 4 D388H, D388N,
389 6 S389P,
392 6 W392R, W392R, W392ins,
384 7
511 7 R511Q, R511W,
385 7 E385K,
383 7
391 8 T391A, T391I,
390 9
508 10 E508G,
515 11
382 11
510 11 H510R, H510Y,
514 11 I514T,
518 11 R518Q, R518G,
512 12
393 12 K393N,
381 12 C381Y,
379 13 W379R, W379R, W379C, W379C, W379G,
380 14 R380S, R380S, R380G,
513 14 T513A, T513S, T513S,
394 14 I394L,
509 15 H509Q, H509Q, H509R,