KCNQ1 Variant I201F Detail

We estimate the penetrance of LQTS for KCNQ1 I201F is 70%. We are unaware of any observations of this variant in individuals. I201F is not present in gnomAD. I201F 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 I201F around 70% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.69 0.997 5 0.964 77
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.

I201F has 50 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
201 0 I201del,
202 5 D202N, D202H,
200 5
204 5 I204M, I204F,
198 5 I198V, I198T,
199 6 S199A,
197 6 P197L,
240 7 H240R, H240P,
205 7 V205M,
236 7 L236Q, L236R,
239 7
203 7 L203P,
196 9
206 9 V206L,
237 10
233 10 L233P,
243 10 R243H, R243C, R243P, R243S,
171 10
194 10 A194P, A194T,
248 11 W248C, W248C, W248R, W248R,
207 11 V207M, V207L, V207L, V207L, V207L, V207del,
232 11
242 11 D242N, D242Y,
208 11 A208V,
235 11 I235N,
241 12 V241F, V241I, V241G,
167 12
238 12 M238V, M238L, M238L,
245 12 G245V,
209 12 S209P,
174 12 R174H, R174C, R174L,
193 12 F193L, F193L, F193L,
275 13 F275del,
244 13
168 13 G168R, G168R, G168R, G168R,
195 13 R195Q, R195W,
234 13 Q234H, Q234H,
170 13
271 13
115 14 E115A, E115G,
164 14
229 14 G229D,
175 14 L175I,
133 14 V133I,
230 15
246 15
267 15 Y267C,
247 15 T247I,
210 15 M210I, M210I, M210I,
130 15