KCNQ1 Variant A399P Detail

We estimate the penetrance of LQTS for KCNQ1 A399P is 14%. We are unaware of any observations of this variant in individuals. A399P is not present in gnomAD. A399P has not been functionally characterized. 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 A399P around 14% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
1.48 0.0 3 0.516 10
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.

A399P 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
399 0 A399S, A399V, A399G,
398 4 K398R,
400 4
397 5 R397W, R397Q, R397G,
401 5 R401W, R401Q,
396 7
402 7
395 8 Y395C,
403 8 H403P,
394 8 I394L,
404 8
393 9 K393N,
405 9
392 10 W392R, W392R, W392ins,
406 10
391 11 T391A, T391I,
407 11
390 11
408 11 P408A,
389 12 S389P,
409 12
388 13 D388H, D388N,
410 13
387 13 P387T,
411 13
386 14 N386K, N386K,
412 14 P412S,
385 14 E385K,
413 14 K413R,
384 15
414 15