KCNQ1 Variant I227N Detail

We estimate the penetrance of LQTS for KCNQ1 I227N is 60%. We are unaware of any observations of this variant in individuals. I227N is not present in gnomAD. I227N 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 I227N around 60% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.18 0.999 -4 0.944 65
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 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.

I227N 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
227 0
226 4 A226V,
228 4
225 5 S225L, S225del,
223 5
222 6
224 6 T224M,
231 6 R231C, R231H, R231S,
229 7 G229D,
230 7
221 9
212 9
144 10 T144A,
143 10 S143F, S143P, S143Y,
285 10
219 10 G219E,
217 10
282 10 L282P,
140 11 S140G, S140R, S140R, S140R,
281 11 Y281C,
153 11 T153M,
216 11 G216R,
220 11 Q220K,
232 11
213 11
215 11 V215M, V215G, V215L, V215L,
233 11 L233P,
234 12 Q234H, Q234H,
278 12 Y278H,
286 12
156 12
149 12
157 12 F157C,
218 12
209 13 S209P,
160 13 E160del, E160K, E160V,
299 13
146 13 E146K, E146G, E146Q,
211 13
152 13
208 13 A208V,
141 13 V141M,
283 14 A283G, A283T,
297 14 G297S, G297D, G297R,
145 14
154 14
298 14 S298I, S298N,
235 14 I235N,
214 14 C214Y,
279 15 F279I,
142 15
136 15