KCNQ1 Variant L250P Detail

We estimate the penetrance of LQTS for KCNQ1 L250P is 70%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. L250P is not present in gnomAD. L250P 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 L250P around 70% (7/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.8 0.995 -3 0.944 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
19716085 2009 1 None 1 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.

L250P has 30 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
250 0 L250H, L250P,
247 6 T247I,
249 7 R249S, R249S,
246 7
245 9 G245V,
248 9 W248C, W248C, W248R, W248R,
268 10 I268V, I268S,
261 10 E261K, E261D, E261D, E261G, E261Q,
242 11 D242N, D242Y,
267 11 Y267C,
260 12
264 12
258 12 H258P, H258N, H258R, H258Y,
262 12 L262P, L262R, L262V,
265 13 T265I,
244 13
355 13
263 13
259 13 R259C, R259H, R259L, R259G,
269 13 G269D, G269S, G269del,
257 13 I257V,
255 13
254 14 V254M, V254L, V254L,
347 14 L347P, L347R,
343 14 P343S, P343L, P343R,
358 14 K358T,
346 14
256 15
271 15
266 15 L266P,