KCNQ1 Variant G246C Detail

We estimate the penetrance of LQTS for KCNQ1 G246C is 74%. We are unaware of any observations of this variant in individuals. G246C is not present in gnomAD. G246C 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 G246C around 74% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-8.75 1.0 -3 0.858 79
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.

G246C has 41 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
246 0
245 3 G245V,
247 4 T247I,
249 5 R249S, R249S,
242 5 D242N, D242Y,
248 6 W248C, W248C, W248R, W248R,
244 7
250 7 L250H, L250P,
264 8
243 9 R243H, R243C, R243P, R243S,
251 9 L251P, L251Q,
241 10 V241F, V241I, V241G,
267 10 Y267C,
260 10
252 10 G252R,
268 10 I268V, I268S,
253 10 S253A, S253P,
198 11 I198V, I198T,
261 11 E261K, E261D, E261D, E261G, E261Q,
263 11
117 11 P117L,
116 12
115 12 E115A, E115G,
239 12
265 12 T265I,
196 12
197 12 P197L,
240 13 H240R, H240P,
254 13 V254M, V254L, V254L,
271 13
351 14 F351L, F351L, F351L, F351S,
358 14 K358T,
118 14
266 14 L266P,
126 14 H126D,
354 14
238 14 M238V, M238L, M238L,
269 15 G269D, G269S, G269del,
199 15 S199A,
130 15
201 15 I201del,