KCNQ1 Variant E295A Detail

We estimate the penetrance of LQTS for KCNQ1 E295A is 63%. We are unaware of any observations of this variant in individuals. E295A is not present in gnomAD. E295A 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 E295A around 63% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.99 0.051 -2 0.63 71
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.

E295A has 28 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
280 10 V280A, V280E,
281 10 Y281C,
285 10
293 11 R293C, R293H,
286 11
321 11
301 12
294 12 V294M,
304 12 W304R, W304R,
319 13 V319L, V319L,
277 13 S277L, S277del, S277P, S277W,
299 13
326 13
297 13 G297S, G297D, G297R,
295 13
282 13 L282P,
302 14 A302V, A302E, A302T,
289 14
322 14 T322M, T322A, T322K,
320 14 P320H, P320A, P320S,
318 14
290 14 E290K,
298 14 S298I, S298N,
308 14 V308F,
276 15 S276del,
300 15 A300T, A300S,
144 15 T144A,
316 15 G316E, G316R, G316R, G316V,