KCNQ1 Variant V308F Detail

We estimate the penetrance of LQTS for KCNQ1 V308F is 81%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. V308F is not present in gnomAD. V308F 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 V308F around 81% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.89 0.999 0 0.926 89
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 1 None 1 None
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.

V308F 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
314 10 G314S, G314D, G314C, G314del,
313 11
312 11 T312del, T312I,
308 11 V308F,
315 12 Y315C, Y315S, Y315N, Y315H, Y315F,
309 12 T309I, T309R,
316 12 G316E, G316R, G316R, G316V,
276 13 S276del,
311 13 T311A, T311I,
277 13 S277L, S277del, S277P, S277W,
280 13 V280A, V280E,
332 14
325 14 G325R, G325R, G325E, G325W,
302 14 A302V, A302E, A302T,
273 14 L273F, L273V, L273R,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
328 14 I328del,
296 14 F296S, F296L, F296L, F296L,
310 14 V310I,
303 15 L303P,
331 15
335 15 F335L, F335L, F335L,
337 15
319 15 V319L, V319L,
298 15 S298I, S298N,