KCNQ1 Variant R293H Detail

We estimate the penetrance of LQTS for KCNQ1 R293H is 38%. This variant was found in a total of 5 carriers in 2 papers or gnomAD, 0 had LQTS. R293H is present in 4 alleles in gnomAD. R293H 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 R293H around 38% (5/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.31 0.834 3 0.524 56
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
22949429 2012 1 1 None None
19841300 2009 1 1 None None
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.

R293H has 12 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
298 11 S298I, S298N,
321 12
288 12
319 13 V319L, V319L,
290 13 E290K,
294 13 V294M,
302 13 A302V, A302E, A302T,
300 14 A300T, A300S,
291 14
287 14 A287E, A287T, A287S,
320 14 P320H, P320A, P320S,
289 14