KCNQ1 Variant M238V Detail

We estimate the penetrance of LQTS for KCNQ1 M238V is 18%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. M238V is present in 2 alleles in gnomAD. M238V has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 M238V around 18% (2/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.89 0.798 4 0.903 19
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: - 2 2 0
VARIANT FEATURES ALONE: - 10 8 2 -
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.

M238V has 62 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
238 0 M238V, M238L, M238L,
239 5
235 6 I235N,
271 6
130 6
133 6 V133I,
134 7 L134P,
241 7 V241F, V241I, V241G,
137 7 L137F, L137P,
236 7 L236Q, L236R,
267 7 Y267C,
240 7 H240R, H240P,
237 8
274 8 I274V,
234 8 Q234H, Q234H,
275 8 F275del,
242 9 D242N, D242Y,
136 10
270 10 F270S,
272 10 G272D, G272S, G272V,
268 10 I268V, I268S,
129 11 V129I,
233 11 L233P,
131 11
232 11
248 11 W248C, W248C, W248R, W248R,
132 11 I132L,
269 11 G269D, G269S, G269del,
135 11
273 11 L273F, L273V, L273R,
138 12
201 12 I201del,
243 12 R243H, R243C, R243P, R243S,
205 12 V205M,
247 12 T247I,
140 12 S140G, S140R, S140R, S140R,
202 12 D202N, D202H,
278 12 Y278H,
198 12 I198V, I198T,
127 13 F127L, F127L, F127L,
167 13
128 13 A128del,
126 13 H126D,
277 13 S277L, S277del, S277P, S277W,
299 13
266 13 L266P,
303 13 L303P,
276 13 S276del,
231 14 R231C, R231H, R231S,
141 14 V141M,
245 14 G245V,
230 14
264 14
163 14
139 14
229 14 G229D,
246 14
160 14 E160del, E160K, E160V,
263 15
279 15 F279I,
265 15 T265I,
204 15 I204M, I204F,