KCNQ1 Variant R518Q Detail

We estimate the penetrance of LQTS for KCNQ1 R518Q is 33%. This variant was found in a total of 10 carriers in 2 papers or gnomAD, 1 had LQTS. R518Q is present in 9 alleles in gnomAD. R518Q 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R518Q around 33% (6/20).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.93 0.784 -1 0.723 59
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
29544605 2018 1 None None None
23631430 2013 1 None None None
LITERATURE, COHORT, AND GNOMAD: - 10 9 1
VARIANT FEATURES ALONE: - 10 5 5 -
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.

R518Q has 41 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
518 0 R518Q, R518G,
380 5 R380S, R380S, R380G,
381 5 C381Y,
514 5 I514T,
515 6
517 6 I517T,
384 6
521 7
377 7
383 7
516 7
392 7 W392R, W392R, W392ins,
519 8 R519H, R519C,
391 8 T391A, T391I,
378 9 A378T,
520 9 M520R,
513 9 T513A, T513S, T513S,
379 9 W379R, W379R, W379C, W379C, W379G,
522 9 Y522S,
512 9
385 10 E385K,
511 10 R511Q, R511W,
382 10
523 11
376 11
389 11 S389P,
394 11 I394L,
387 11 P387T,
386 12 N386K, N386K,
510 12 H510R, H510Y,
393 12 K393N,
390 12
373 12 S373P,
524 12 V524G,
374 13 L374H, L374F,
525 13 A525T, A525V,
375 13
508 14 E508G,
388 14 D388H, D388N,
526 15 K526Q, K526E,
372 15