KCNQ1 Variant L262V Detail

We estimate the penetrance of LQTS for KCNQ1 L262V is 55%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. L262V is not present in gnomAD. L262V 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L262V around 55% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.92 0.999 2 0.94 56
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.

L262V has 22 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
259 7 R259C, R259H, R259L, R259G,
251 11 L251P, L251Q,
265 11 T265I,
339 12 F339del, F339S,
254 12 V254M, V254L, V254L,
250 12 L250H, L250P,
255 13
264 13
252 14 G252R,
354 14
266 14 L266P,
247 14 T247I,
253 14 S253A, S253P,
268 14 I268V, I268S,
335 14 F335L, F335L, F335L,
336 14 A336S,
345 14 G345R, G345R, G345A,
263 15
257 15 I257V,
342 15 L342F, L342P,
269 15 G269D, G269S, G269del,
334 15 V334A,