KCNQ1 Variant I268V Detail

We estimate the penetrance of LQTS for KCNQ1 I268V is 61%. This variant was found in a total of 3 carriers in 1 papers or gnomAD, 1 had LQTS. I268V is present in 2 alleles in gnomAD. I268V 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 I268V around 61% (7/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.97 0.951 1 0.674 67
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
32893267 2020 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 3 2 1
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.

I268V has 43 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
268 0 I268V, I268S,
269 4 G269D, G269S, G269del,
267 5 Y267C,
271 5
264 6
248 7 W248C, W248C, W248R, W248R,
247 7 T247I,
251 7 L251P, L251Q,
272 7 G272D, G272S, G272V,
242 9 D242N, D242Y,
239 9
250 10 L250H, L250P,
273 10 L273F, L273V, L273R,
238 10 M238V, M238L, M238L,
246 10
274 10 I274V,
275 11 F275del,
245 11 G245V,
241 12 V241F, V241I, V241G,
249 12 R249S, R249S,
351 12 F351L, F351L, F351L, F351S,
276 13 S276del,
235 13 I235N,
253 13 S253A, S253P,
236 13 L236Q, L236R,
240 14 H240R, H240P,
266 14 L266P,
130 14
343 14 P343S, P343L, P343R,
334 14 V334A,
338 14 S338F,
198 14 I198V, I198T,
262 14 L262P, L262R, L262V,
243 14 R243H, R243C, R243P, R243S,
255 14
335 14 F335L, F335L, F335L,
339 14 F339del, F339S,
347 15 L347P, L347R,
277 15 S277L, S277del, S277P, S277W,
344 15 A344V, A344E,
265 15 T265I,
252 15 G252R,
306 15 G306V, G306R, G306R,