KCNQ1 Variant L303P Detail

We estimate the penetrance of LQTS for KCNQ1 L303P is 72%. This variant was found in a total of 2 carriers in 3 papers or gnomAD, 2 had LQTS. L303P is not present in gnomAD. L303P 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 L303P around 72% (8/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.81 1.0 -5 0.962 74
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
33614747 2021 1 None 1 None
32893267 2020 1 None 1 None
19716085 2009 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 2 0 2
VARIANT FEATURES ALONE: - 10 4 6 -
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.

L303P has 56 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
303 0 L303P,
302 4 A302V, A302E, A302T,
300 5 A300T, A300S,
299 5
274 7 I274V,
273 7 L273F, L273V, L273R,
301 7
298 8 S298I, S298N,
141 8 V141M,
281 9 Y281C,
296 10 F296S, F296L, F296L, F296L,
278 10 Y278H,
272 10 G272D, G272S, G272V,
275 10 F275del,
270 10 F270S,
137 11 L137F, L137P,
277 11 S277L, S277del, S277P, S277W,
297 11 G297S, G297D, G297R,
144 11 T144A,
140 11 S140G, S140R, S140R, S140R,
306 11 G306V, G306R, G306R,
235 11 I235N,
138 11
145 12
271 12
231 12 R231C, R231H, R231S,
276 12 S276del,
280 12 V280A, V280E,
305 12 W305S, W305L, W305C, W305C, W305R, W305R,
142 12
269 13 G269D, G269S, G269del,
282 13 L282P,
309 13 T309I, T309R,
238 13 M238V, M238L, M238L,
329 13 A329T,
143 14 S143F, S143P, S143Y,
134 14 L134P,
234 14 Q234H, Q234H,
285 14
340 14 F340del, F340L, F340L, F340L, F340S,
320 14 P320H, P320A, P320S,
310 14 V310I,
328 14 I328del,
325 14 G325R, G325R, G325E, G325W,
232 14
333 14
318 14
332 14
279 14 F279I,
330 15
136 15
284 15 E284K,
139 15
319 15 V319L, V319L,
294 15 V294M,
326 15