KCNQ1 Variant L251P Detail

We estimate the penetrance of LQTS for KCNQ1 L251P is 75%. This variant was found in a total of 3 carriers in 2 papers or gnomAD, 3 had LQTS. L251P is not present in gnomAD. L251P has been functionally characterized in 1 papers. 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 L251P around 75% (9/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.8 0.998 -5 0.975 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
32893267 2020 3 None 3 None
12710526 2003 None None None None
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
12710526 CHO 0 None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
12710526 CHO 9 0.0 1.0 1.0

L251P 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,