KCNQ1 Variant G245R Detail

We estimate the penetrance of LQTS for KCNQ1 G245R is 76%. We are unaware of any observations of this variant in individuals. G245R is not present in gnomAD. G245R has been functionally characterized in 1 papers. 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 G245R around 76% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.78 0.991 -3 0.939 82
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
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
30571187 HEK 2 None None 0.0

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
30571187 HEK 28 9.0 None 0.798745532

G245R has 44 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
245 0 G245V,
246 3
242 5 D242N, D242Y,
248 5 W248C, W248C, W248R, W248R,
249 5 R249S, R249S,
244 5
247 5 T247I,
243 7 R243H, R243C, R243P, R243S,
198 8 I198V, I198T,
250 9 L250H, L250P,
196 9
241 9 V241F, V241I, V241G,
197 9 P197L,
239 10
264 10
251 10 L251P, L251Q,
252 10 G252R,
267 10 Y267C,
115 10 E115A, E115G,
268 11 I268V, I268S,
253 11 S253A, S253P,
240 11 H240R, H240P,
116 12
199 12 S199A,
201 12 I201del,
117 12 P117L,
271 13
202 13 D202N, D202H,
260 13
265 13 T265I,
200 13
263 14
238 14 M238V, M238L, M238L,
261 14 E261K, E261D, E261D, E261G, E261Q,
126 14 H126D,
193 14 F193L, F193L, F193L,
254 14 V254M, V254L, V254L,
114 14
174 14 R174H, R174C, R174L,
111 14 Y111C,
130 15
255 15
236 15 L236Q, L236R,
269 15 G269D, G269S, G269del,