KCNQ1 Variant G269C Detail

We estimate the penetrance of LQTS for KCNQ1 G269C is 67%. We are unaware of any observations of this variant in individuals. G269C is not present in gnomAD. G269C 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 G269C around 67% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.75 0.998 0 0.928 73
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
30758498 2019 1 None 1 None
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.

G269C has 40 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
269 0 G269D, G269S, G269del,
268 4 I268V, I268S,
272 5 G272D, G272S, G272V,
271 5
273 6 L273F, L273V, L273R,
267 7 Y267C,
274 8 I274V,
264 9
275 10 F275del,
276 10 S276del,
306 11 G306V, G306R, G306R,
248 11 W248C, W248C, W248R, W248R,
247 11 T247I,
238 11 M238V, M238L, M238L,
334 11 V334A,
277 11 S277L, S277del, S277P, S277W,
239 12
336 12 A336S,
335 12 F335L, F335L, F335L,
339 13 F339del, F339S,
303 13 L303P,
235 13 I235N,
333 13
242 13 D242N, D242Y,
250 13 L250H, L250P,
261 14 E261K, E261D, E261D, E261G, E261Q,
251 14 L251P, L251Q,
266 14 L266P,
330 14
279 14 F279I,
241 14 V241F, V241I, V241G,
331 14
351 14 F351L, F351L, F351L, F351S,
278 14 Y278H,
332 14
246 15
236 15 L236Q, L236R,
347 15 L347P, L347R,
270 15 F270S,
245 15 G245V,