KCNQ1 Variant G272C Detail

We estimate the penetrance of LQTS for KCNQ1 G272C is 59%. We are unaware of any observations of this variant in individuals. G272C is not present in gnomAD. G272C 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 G272C around 59% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.18 0.803 -1 0.817 62
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 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.

G272C 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
272 0 G272D, G272S, G272V,
273 4 L273F, L273V, L273R,
271 5
269 5 G269D, G269S, G269del,
274 5 I274V,
275 5 F275del,
276 6 S276del,
268 7 I268V, I268S,
277 8 S277L, S277del, S277P, S277W,
339 8 F339del, F339S,
267 9 Y267C,
279 9 F279I,
235 9 I235N,
278 10 Y278H,
238 10 M238V, M238L, M238L,
303 10 L303P,
239 10
280 12 V280A, V280E,
236 12 L236Q, L236R,
335 12 F335L, F335L, F335L,
248 12 W248C, W248C, W248R, W248R,
336 12 A336S,
332 12
302 12 A302V, A302E, A302T,
270 12 F270S,
232 12
333 12
299 12
334 12 V334A,
340 13 F340del, F340L, F340L, F340L, F340S,
310 13 V310I,
251 13 L251P, L251Q,
307 13 V307L, V307L,
264 13
337 13
331 13
330 13
311 14 T311A, T311I,
247 14 T247I,
137 14 L137F, L137P,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
266 14 L266P,
338 14 S338F,
329 14 A329T,
306 14 G306V, G306R, G306R,
242 14 D242N, D242Y,
282 15 L282P,
325 15 G325R, G325R, G325E, G325W,
234 15 Q234H, Q234H,
300 15 A300T, A300S,
328 15 I328del,
241 15 V241F, V241I, V241G,