KCNQ1 Variant L251V Detail

We estimate the penetrance of LQTS for KCNQ1 L251V is 62%. We are unaware of any observations of this variant in individuals. L251V is not present in gnomAD. L251V 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L251V around 62% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.92 1.0 -1 0.838 74
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 4 6 -
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.

L251V has 40 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
268 7 I268V, I268S,
247 7 T247I,
248 8 W248C, W248C, W248R, W248R,
249 9 R249S, R249S,
251 9 L251P, L251Q,
246 9
269 10 G269D, G269S, G269del,
245 10 G245V,
267 10 Y267C,
255 11
254 11 V254M, V254L, V254L,
252 11 G252R,
262 11 L262P, L262R, L262V,
250 12 L250H, L250P,
242 12 D242N, D242Y,
258 12 H258P, H258N, H258R, H258Y,
271 12
347 12 L347P, L347R,
253 13 S253A, S253P,
261 13 E261K, E261D, E261D, E261G, E261Q,
351 13 F351L, F351L, F351L, F351S,
265 13 T265I,
272 13 G272D, G272S, G272V,
257 13 I257V,
263 14
264 14
343 14 P343S, P343L, P343R,
259 14 R259C, R259H, R259L, R259G,
266 14 L266P,
256 14
346 14
350 14 G350V, G350R, G350R, G350W,
348 14
344 14 A344V, A344E,
345 14 G345R, G345R, G345A,
342 14 L342F, L342P,
260 14
239 14
355 15
335 15 F335L, F335L, F335L,