KCNQ1 Variant F296S Detail

We estimate the penetrance of LQTS for KCNQ1 F296S is 49%. This variant was found in a total of 7 carriers in 5 papers or gnomAD, 6 had LQTS. F296S is not present in gnomAD. F296S has been functionally characterized in 1 papers. 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 F296S around 49% (8/17).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.48 1.0 -2 0.964 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
32893267 2020 5 None 5 None
29688407 2018 1 1 None None
19808498 2009 1 None 1 None
19490272 2009 1 None 1 None
17470695 2007 2 None 2 None
LITERATURE, COHORT, AND GNOMAD: - 7 1 6
VARIANT FEATURES ALONE: - 10 8 2 -
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19808498 CHO 12 -10.0 None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
19808498 CHO None None None

F296S 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,