KCNQ1 Variant A302P Detail

We estimate the penetrance of LQTS for KCNQ1 A302P is 74%. We are unaware of any observations of this variant in individuals. A302P is not present in gnomAD. A302P 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 A302P around 74% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.86 0.998 -3 0.954 81
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.

A302P has 53 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
302 0 A302V, A302E, A302T,
303 4 L303P,
301 5
277 5 S277L, S277del, S277P, S277W,
300 5 A300T, A300S,
299 5
296 6 F296S, F296L, F296L, F296L,
306 6 G306V, G306R, G306R,
281 6 Y281C,
298 7 S298I, S298N,
276 8 S276del,
297 8 G297S, G297D, G297R,
273 9 L273F, L273V, L273R,
274 9 I274V,
278 9 Y278H,
141 10 V141M,
279 10 F279I,
282 11 L282P,
144 11 T144A,
285 11
294 11 V294M,
275 12 F275del,
145 12
231 12 R231C, R231H, R231S,
272 12 G272D, G272S, G272V,
326 12
287 12 A287E, A287T, A287S,
320 13 P320H, P320A, P320S,
140 13 S140G, S140R, S140R, S140R,
304 13 W304R, W304R,
315 13 Y315C, Y315S, Y315N, Y315H, Y315F,
329 13 A329T,
235 13 I235N,
319 13 V319L, V319L,
325 13 G325R, G325R, G325E, G325W,
293 13 R293C, R293H,
330 14
286 14
137 14 L137F, L137P,
270 14 F270S,
142 14
327 14 T327A, T327S, T327S,
143 14 S143F, S143P, S143Y,
280 14 V280A, V280E,
321 14
138 14
322 15 T322M, T322A, T322K,
271 15
328 15 I328del,
232 15
307 15 V307L, V307L,
228 15
288 15