KCNQ1 Variant R228K Detail

We estimate the penetrance of LQTS for KCNQ1 R228K is 57%. We are unaware of any observations of this variant in individuals. R228K is not present in gnomAD. R228K 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R228K around 57% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.85 0.998 1 0.919 61
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 5 5 -
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.

R228K has 52 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
228 0
227 4
225 5 S225L, S225del,
229 5 G229D,
224 6 T224M,
231 6 R231C, R231H, R231S,
226 6 A226V,
282 7 L282P,
223 8
230 8
232 9
285 9
278 9 Y278H,
281 9 Y281C,
222 9
221 10
283 10 A283G, A283T,
212 10
233 10 L233P,
279 11 F279I,
286 11
144 11 T144A,
234 12 Q234H, Q234H,
299 12
140 12 S140G, S140R, S140R, S140R,
235 12 I235N,
208 12 A208V,
143 12 S143F, S143P, S143Y,
220 12 Q220K,
280 13 V280A, V280E,
219 13 G219E,
209 13 S209P,
284 13 E284K,
211 13
275 14 F275del,
236 14 L236Q, L236R,
213 14
215 14 V215M, V215G, V215L, V215L,
277 14 S277L, S277del, S277P, S277W,
297 14 G297S, G297D, G297R,
141 14 V141M,
216 14 G216R,
298 14 S298I, S298N,
217 14
287 15 A287E, A287T, A287S,
324 15
160 15 E160del, E160K, E160V,
205 15 V205M,
296 15 F296S, F296L, F296L, F296L,
302 15 A302V, A302E, A302T,
153 15 T153M,
276 15 S276del,