KCNQ1 Variant F332V Detail

We estimate the penetrance of LQTS for KCNQ1 F332V is 57%. We are unaware of any observations of this variant in individuals. F332V is not present in gnomAD. F332V 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 F332V around 57% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.5 0.998 1 0.899 61
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.

F332V has 32 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 0
335 6 F335L, F335L, F335L,
328 6 I328del,
279 7 F279I,
275 8 F275del,
280 9 V280A, V280E,
325 10 G325R, G325R, G325E, G325W,
278 10 Y278H,
324 12
307 12 V307L, V307L,
282 13 L282P,
320 13 P320H, P320A, P320S,
283 13 A283G, A283T,
310 13 V310I,
235 13 I235N,
330 13
340 13 F340del, F340L, F340L, F340L, F340S,
232 14
334 14 V334A,
308 14 V308F,
306 14 G306V, G306R, G306R,
273 14 L273F, L273V, L273R,
270 14 F270S,
284 14 E284K,
331 14
322 14 T322M, T322A, T322K,
281 15 Y281C,
329 15 A329T,
323 15
304 15 W304R, W304R,
236 15 L236Q, L236R,
269 15 G269D, G269S, G269del,