KCNQ1 Variant A194P Detail

We estimate the penetrance of LQTS for KCNQ1 A194P is 50%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. A194P is not present in gnomAD. A194P 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A194P around 50% (5/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.56 1.0 -4 0.93 51
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
21063070 2010 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
VARIANT FEATURES ALONE: - 10 6 4 -
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.

A194P has 43 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
194 0 A194P, A194T,
193 5 F193L, F193L, F193L,
199 5 S199A,
195 5 R195Q, R195W,
191 6
200 6
196 6
175 8 L175I,
197 8 P197L,
171 8
189 8 G189R, G189R, G189E,
192 8 R192C, R192H,
203 8 L203P,
190 8 R190W, R190Q, R190L,
184 9 Y184S, Y184C, Y184D, Y184H,
198 9 I198V, I198T,
202 9 D202N, D202H,
201 10 I201del,
178 10 A178T, A178del,
187 10 L187P, L187F,
174 10 R174H, R174C, R174L,
204 11 I204M, I204F,
183 11 K183R,
188 11 W188C, W188C, W188G, W188S,
172 11 V172M, V172E,
186 12 G186R, G186D,
115 12 E115A, E115G,
177 12 S177F,
244 13
243 13 R243H, R243C, R243P, R243S,
181 13 R181C,
185 13 V185L, V185L, V185M, V185del,
206 13 V206L,
111 13 Y111C,
173 13
176 13
179 13 G179S,
168 13 G168R, G168R, G168R, G168R,
240 14 H240R, H240P,
205 14 V205M,
207 14 V207M, V207L, V207L, V207L, V207L, V207del,
170 14
114 14