KCNQ1 Variant D242A Detail

We estimate the penetrance of LQTS for KCNQ1 D242A is 75%. We are unaware of any observations of this variant in individuals. D242A is not present in gnomAD. D242A 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 D242A around 75% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.78 0.989 1 0.848 80
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.

D242A has 57 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
242 0 D242N, D242Y,
245 5 G245V,
241 5 V241F, V241I, V241G,
248 5 W248C, W248C, W248R, W248R,
243 5 R243H, R243C, R243P, R243S,
247 5 T247I,
246 5
239 7
244 7
267 7 Y267C,
198 7 I198V, I198T,
240 8 H240R, H240P,
268 9 I268V, I268S,
249 9 R249S, R249S,
238 9 M238V, M238L, M238L,
264 10
271 10
130 10
115 10 E115A, E115G,
126 11 H126D,
201 11 I201del,
197 11 P197L,
196 11
250 11 L250H, L250P,
117 11 P117L,
202 11 D202N, D202H,
251 12 L251P, L251Q,
199 12 S199A,
263 12
236 12 L236Q, L236R,
265 13 T265I,
116 13
129 13 V129I,
114 13
269 13 G269D, G269S, G269del,
174 13 R174H, R174C, R174L,
252 13 G252R,
133 13 V133I,
237 13
123 13
266 14 L266P,
260 14
127 14 F127L, F127L, F127L,
200 14
235 14 I235N,
270 14 F270S,
272 14 G272D, G272S, G272V,
275 14 F275del,
261 14 E261K, E261D, E261D, E261G, E261Q,
134 14 L134P,
253 14 S253A, S253P,
125 15
122 15 C122Y,
170 15
118 15
111 15 Y111C,
167 15