KCNQ1 Variant F335C Detail

We estimate the penetrance of LQTS for KCNQ1 F335C is 65%. We are unaware of any observations of this variant in individuals. F335C is not present in gnomAD. F335C 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 F335C around 65% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.45 0.958 2 0.925 70
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
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.

F335C 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
332 6
275 11 F275del,
328 11 I328del,
266 12 L266P,
255 12
269 12 G269D, G269S, G269del,
279 12 F279I,
270 12 F270S,
252 13 G252R,
307 13 V307L, V307L,
327 13 T327A, T327S, T327S,
265 13 T265I,
248 13 W248C, W248C, W248R, W248R,
273 14 L273F, L273V, L273R,
272 14 G272D, G272S, G272V,
262 14 L262P, L262R, L262V,
278 14 Y278H,
280 14 V280A, V280E,
268 14 I268V, I268S,
330 15
306 15 G306V, G306R, G306R,
325 15 G325R, G325R, G325E, G325W,
308 15 V308F,
343 15 P343S, P343L, P343R,
337 15