KCNQ1 Variant F340del Detail

We estimate the penetrance of LQTS for KCNQ1 F340del is 83%. This variant was found in a total of 9 carriers in 4 papers or gnomAD, 8 had LQTS. F340del is present in 1 alleles in gnomAD. F340del has not been functionally characterized. This residue is located in a NA 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 F340del around 83% (15/19).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
69
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 6 None 6 None
30758498 2019 5 None 2 None
24606995 2014 1 None 1 None
16922724 2006 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 9 1 8
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.

F340del has 37 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
340 8 F340del, F340L, F340L, F340L, F340S,
337 9
341 9 A341V, A341E,
338 10 S338F,
335 10 F335L, F335L, F335L,
336 10 A336S,
310 11 V310I,
312 11 T312del, T312I,
311 11 T311A, T311I,
339 11 F339del, F339S,
267 11 Y267C,
269 12 G269D, G269S, G269del,
342 12 L342F, L342P,
334 12 V334A,
274 12 I274V,
343 12 P343S, P343L, P343R,
333 12
272 12 G272D, G272S, G272V,
344 13 A344V, A344E,
266 13 L266P,
265 13 T265I,
309 13 T309I, T309R,
332 13
307 13 V307L, V307L,
270 13 F270S,
268 13 I268V, I268S,
330 14
273 14 L273F, L273V, L273R,
345 14 G345R, G345R, G345A,
303 14 L303P,
313 14
306 14 G306V, G306R, G306R,
329 14 A329T,
331 14
276 14 S276del,
308 15 V308F,
271 15