KCNQ1 Variant E284D Detail

We estimate the penetrance of LQTS for KCNQ1 E284D is 74%. We are unaware of any observations of this variant in individuals. E284D is not present in gnomAD. E284D 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 E284D around 74% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.92 1.0 0 0.791 78
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: - 0 0 0
VARIANT FEATURES ALONE: - 10 3 7 -
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.

E284D 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
284 0 E284K,
283 4 A283G, A283T,
287 5 A287E, A287T, A287S,
322 5 T322M, T322A, T322K,
280 6 V280A, V280E,
325 7 G325R, G325R, G325E, G325W,
285 7
281 7 Y281C,
286 7
282 8 L282P,
324 8
288 8
328 10 I328del,
279 10 F279I,
277 10 S277L, S277del, S277P, S277W,
278 11 Y278H,
296 11 F296S, F296L, F296L, F296L,
276 11 S276del,
321 12
320 12 P320H, P320A, P320S,
295 12
318 12
326 12
301 13
228 13
302 13 A302V, A302E, A302T,
317 13 D317N, D317G, D317Y,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
304 14 W304R, W304R,
292 14 G292D,
297 14 G297S, G297D, G297R,
294 14 V294M,
144 14 T144A,
319 14 V319L, V319L,
298 14 S298I, S298N,
332 14
231 14 R231C, R231H, R231S,
300 15 A300T, A300S,
323 15
293 15 R293C, R293H,
289 15