KCNQ1 Variant D317E Detail

We estimate the penetrance of LQTS for KCNQ1 D317E is 79%. We are unaware of any observations of this variant in individuals. D317E is not present in gnomAD. D317E 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D317E around 79% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.73 1.0 1 0.875 87
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
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.

D317E has 20 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
316 9 G316E, G316R, G316R, G316V,
319 11 V319L, V319L,
317 12 D317N, D317G, D317Y,
314 12 G314S, G314D, G314C, G314del,
315 13 Y315C, Y315S, Y315N, Y315H, Y315F,
320 13 P320H, P320A, P320S,
318 14
322 14 T322M, T322A, T322K,
284 14 E284K,
321 14
326 14
325 14 G325R, G325R, G325E, G325W,
288 14
290 14 E290K,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
289 14
329 15 A329T,
294 15 V294M,
287 15 A287E, A287T, A287S,
295 15