KCNQ1 Variant Y395C Detail

We estimate the penetrance of LQTS for KCNQ1 Y395C is 19%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. Y395C is present in 2 alleles in gnomAD. Y395C 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 Y395C around 19% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.58 1.0 -3 0.847 20
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: - 2 2 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.

Y395C 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
395 0 Y395C,
394 4 I394L,
396 4
393 5 K393N,
397 5 R397W, R397Q, R397G,
392 7 W392R, W392R, W392ins,
398 7 K398R,
391 8 T391A, T391I,
399 8 A399S, A399V, A399G,
390 8
400 8
389 9 S389P,
401 9 R401W, R401Q,
388 10 D388H, D388N,
402 10
387 11 P387T,
403 11 H403P,
386 11 N386K, N386K,
404 11
385 12 E385K,
405 12
384 13
406 13
383 13
407 13
382 14
408 14 P408A,
381 14 C381Y,
409 14
380 15 R380S, R380S, R380G,
410 15