KCNQ1 Variant I274V Detail

We estimate the penetrance of LQTS for KCNQ1 I274V is 11%. This variant was found in a total of 50 carriers in 6 papers or gnomAD, 1 had LQTS. I274V is present in 49 alleles in gnomAD. I274V 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 I274V around 11% (6/60).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.97 0.894 1 0.846 49
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
29197658 2018 1 None 1 None
19716085 2009 1 None 1 None
19490272 2009 1 None 1 None
18222468 2008 None None None None
17470695 2007 1 None 1 None
17210839 2007 1 None None None
LITERATURE, COHORT, AND GNOMAD: - 50 49 1
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.

I274V has 56 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
274 0 I274V,
273 4 L273F, L273V, L273R,
275 5 F275del,
272 5 G272D, G272S, G272V,
271 5
277 6 S277L, S277del, S277P, S277W,
235 6 I235N,
276 7 S276del,
303 7 L303P,
270 7 F270S,
238 8 M238V, M238L, M238L,
278 8 Y278H,
299 8
269 8 G269D, G269S, G269del,
137 9 L137F, L137P,
306 9 G306V, G306R, G306R,
279 9 F279I,
302 9 A302V, A302E, A302T,
267 10 Y267C,
236 10 L236Q, L236R,
232 10
239 10
268 10 I268V, I268S,
234 11 Q234H, Q234H,
280 11 V280A, V280E,
300 11 A300T, A300S,
310 11 V310I,
141 11 V141M,
134 11 L134P,
140 12 S140G, S140R, S140R, S140R,
231 12 R231C, R231H, R231S,
340 12 F340del, F340L, F340L, F340L, F340S,
281 12 Y281C,
138 12
133 12 V133I,
266 12 L266P,
237 13
339 13 F339del, F339S,
233 13 L233P,
130 13
282 13 L282P,
136 13
305 13 W305S, W305L, W305C, W305C, W305R, W305R,
301 13
298 14 S298I, S298N,
229 14 G229D,
240 14 H240R, H240P,
241 14 V241F, V241I, V241G,
248 14 W248C, W248C, W248R, W248R,
144 14 T144A,
330 14
265 14 T265I,
296 14 F296S, F296L, F296L, F296L,
135 15
230 15
331 15