KCNQ1 Variant F296I Detail

We estimate the penetrance of LQTS for KCNQ1 F296I is 30%. We are unaware of any observations of this variant in individuals. F296I is not present in gnomAD. F296I has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F296I around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.74 0.995 -3 0.933 33
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.

F296I 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
297 6 G297S, G297D, G297R,
281 6 Y281C,
294 7 V294M,
287 7 A287E, A287T, A287S,
285 8
283 8 A283G, A283T,
299 9
277 9 S277L, S277del, S277P, S277W,
286 10
282 10 L282P,
276 12 S276del,
144 12 T144A,
278 12 Y278H,
279 12 F279I,
320 12 P320H, P320A, P320S,
321 12
292 12 G292D,
326 13
145 13
141 13 V141M,
304 13 W304R, W304R,
322 14 T322M, T322A, T322K,
231 14 R231C, R231H, R231S,
273 14 L273F, L273V, L273R,
284 14 E284K,
325 14 G325R, G325R, G325E, G325W,
274 14 I274V,
301 15
228 15
296 15 F296S, F296L, F296L, F296L,