KCNQ1 Variant Q244E Detail

We estimate the penetrance of LQTS for KCNQ1 Q244E is 73%. We are unaware of any observations of this variant in individuals. Q244E is not present in gnomAD. Q244E 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 Q244E around 73% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.67 0.803 -2 0.857 78
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.

Q244E has 48 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
244 0
245 5 G245V,
243 5 R243H, R243C, R243P, R243S,
115 6 E115A, E115G,
246 7
242 7 D242N, D242Y,
196 7
116 7
198 7 I198V, I198T,
249 8 R249S, R249S,
117 9 P117L,
111 9 Y111C,
248 9 W248C, W248C, W248R, W248R,
197 10 P197L,
247 10 T247I,
199 10 S199A,
193 10 F193L, F193L, F193L,
241 10 V241F, V241I, V241G,
114 10
174 11 R174H, R174C, R174L,
112 11
181 11 R181C,
240 11 H240R, H240P,
184 12 Y184S, Y184C, Y184D, Y184H,
183 12 K183R,
202 12 D202N, D202H,
126 12 H126D,
118 13
239 13
178 13 A178T, A178del,
194 13 A194P, A194T,
201 13 I201del,
250 13 L250H, L250P,
200 13
177 13 S177F,
113 13
180 14
122 14 C122Y,
171 14
170 14
267 14 Y267C,
175 14 L175I,
264 14
110 14 V110I,
252 15 G252R,
108 15 G108S,
253 15 S253A, S253P,
119 15 G119R, G119V,