KCNQ1 Variant V254L Detail

We estimate the penetrance of LQTS for KCNQ1 V254L is 79%. This variant was found in a total of 3 carriers in 2 papers or gnomAD, 3 had LQTS. V254L is not present in gnomAD. V254L 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V254L around 79% (10/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.92 0.995 0 0.907 80
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
14678125 2003 2 None 2 None
LITERATURE, COHORT, AND GNOMAD: - 3 0 3
VARIANT FEATURES ALONE: - 10 3 7 -
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.

V254L has 25 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
261 10 E261K, E261D, E261D, E261G, E261Q,
249 10 R249S, R249S,
355 11
250 11 L250H, L250P,
251 11 L251P, L251Q,
262 12 L262P, L262R, L262V,
260 12
265 12 T265I,
257 13 I257V,
258 13 H258P, H258N, H258R, H258Y,
264 13
358 13 K358T,
248 13 W248C, W248C, W248R, W248R,
255 13
254 14 V254M, V254L, V254L,
346 14
245 14 G245V,
259 14 R259C, R259H, R259L, R259G,
349 14 S349W,
263 14
345 14 G345R, G345R, G345A,
342 14 L342F, L342P,
351 14 F351L, F351L, F351L, F351S,
339 14 F339del, F339S,
359 15 Q359del,