KCNQ1 Variant V241F Detail

We estimate the penetrance of LQTS for KCNQ1 V241F is 36%. This variant was found in a total of 3 carriers in 2 papers or gnomAD, 0 had LQTS. V241F is not present in gnomAD. V241F 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 V241F around 36% (4/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.31 0.982 1 0.84 46
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
25230101 2014 None None None None
23989646 2014 3 3 None 3 AF/Bradycardia
LITERATURE, COHORT, AND GNOMAD: - 3 3 0
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.

V241F has 65 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
241 0 V241F, V241I, V241G,
242 5 D242N, D242Y,
130 6
243 6 R243H, R243C, R243P, R243S,
240 6 H240R, H240P,
239 7
238 7 M238V, M238L, M238L,
126 7 H126D,
267 8 Y267C,
129 8 V129I,
133 9 V133I,
247 9 T247I,
248 9 W248C, W248C, W248R, W248R,
245 9 G245V,
198 9 I198V, I198T,
127 10 F127L, F127L, F127L,
246 10
244 10
128 10 A128del,
134 10 L134P,
271 10
237 10
131 11
123 11
115 11 E115A, E115G,
117 11 P117L,
202 11 D202N, D202H,
125 11
236 11 L236Q, L236R,
114 11
132 11 I132L,
268 12 I268V, I268S,
201 12 I201del,
167 12
264 12
235 12 I235N,
170 12
174 12 R174H, R174C, R174L,
122 12 C122Y,
124 13
199 13 S199A,
137 13 L137F, L137P,
263 13
113 13
205 14 V205M,
270 14 F270S,
234 14 Q234H, Q234H,
197 14 P197L,
196 14
166 14 F166V,
249 14 R249S, R249S,
274 14 I274V,
136 14
116 14
269 14 G269D, G269S, G269del,
275 14 F275del,
266 14 L266P,
135 14
119 15 G119R, G119V,
118 15
163 15
171 15
233 15 L233P,
265 15 T265I,
272 15 G272D, G272S, G272V,