KCNQ1 Variant R511Q Detail

We estimate the penetrance of LQTS for KCNQ1 R511Q is 34%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. R511Q is present in 2 alleles in gnomAD. R511Q has not been functionally characterized. This residue is located in a Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R511Q around 34% (4/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.45 0.998 -1 0.859 41
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 6 4 -
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.

R511Q has 26 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
511 0 R511Q, R511W,
510 4 H510R, H510Y,
508 5 E508G,
392 6 W392R, W392R, W392ins,
512 6
514 7 I514T,
387 7 P387T,
509 8 H509Q, H509Q, H509R,
513 8 T513A, T513S, T513S,
515 9
384 9
388 10 D388H, D388N,
518 10 R518Q, R518G,
386 11 N386K, N386K,
385 11 E385K,
389 11 S389P,
391 11 T391A, T391I,
383 11
516 11
517 12 I517T,
393 12 K393N,
394 12 I394L,
381 13 C381Y,
390 13
380 14 R380S, R380S, R380G,
519 14 R519H, R519C,