KCNQ1 Variant D301E Detail

We estimate the penetrance of LQTS for KCNQ1 D301E is 39%. We are unaware of any observations of this variant in individuals. D301E is not present in gnomAD. D301E 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D301E around 39% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.13 0.978 0 0.615 47
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 7 3 -
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.

D301E has 44 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
301 0
300 4 A300T, A300S,
298 4 S298I, S298N,
302 5 A302V, A302E, A302T,
297 6 G297S, G297D, G297R,
303 7 L303P,
299 7
281 8 Y281C,
277 9 S277L, S277del, S277P, S277W,
145 10
144 10 T144A,
141 10 V141M,
293 10 R293C, R293H,
296 10 F296S, F296L, F296L, F296L,
285 11
295 11
320 12 P320H, P320A, P320S,
319 12 V319L, V319L,
284 12 E284K,
142 13
280 13 V280A, V280E,
321 13
273 13 L273F, L273V, L273R,
278 13 Y278H,
274 13 I274V,
143 13 S143F, S143P, S143Y,
140 13 S140G, S140R, S140R, S140R,
294 13 V294M,
282 13 L282P,
306 14 G306V, G306R, G306R,
146 14 E146K, E146G, E146Q,
231 14 R231C, R231H, R231S,
326 14
325 14 G325R, G325R, G325E, G325W,
147 14 Q147R,
322 14 T322M, T322A, T322K,
287 14 A287E, A287T, A287S,
304 14 W304R, W304R,
289 14
148 14
283 14 A283G, A283T,
138 15
329 15 A329T,
309 15 T309I, T309R,