KCNQ1 Variant A399S Detail

We estimate the penetrance of LQTS for KCNQ1 A399S is 5%. This variant was found in a total of 22 carriers in 1 papers or gnomAD, 0 had LQTS. A399S is present in 22 alleles in gnomAD. A399S 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 A399S around 5% (1/32).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.01 0.002 0 0.628 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
29197658 2018 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 22 22 0
VARIANT FEATURES ALONE: - 10 9 1 -
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.

A399S 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