KCNQ1 Variant F339S Detail

We estimate the penetrance of LQTS for KCNQ1 F339S is 77%. This variant was found in a total of 4 carriers in 7 papers or gnomAD, 4 had LQTS. F339S is not present in gnomAD. F339S has been functionally characterized in 2 papers. 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 F339S around 77% (10/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.57 1.0 -3 0.955 77
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 3 None 3 None
30758498 2019 3 None None None
24667783 2015 3 None 3 None
23291057 2013 1 None 1 None
19808498 2009 1 None 1 None
17224687 2007 1 None 1 None
17192539 2006 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.

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)
23291057 Oocytes 4 1.0 None None
19808498 CHO 24 0.0 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)
23291057 Oocytes 15 8.0 None None
19808498 CHO None None None

F339S has 18 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
271 10
250 11 L250H, L250P,
266 12 L266P,
247 12 T247I,
262 12 L262P, L262R, L262V,
248 12 W248C, W248C, W248R, W248R,
276 13 S276del,
255 13
274 13 I274V,
275 13 F275del,
270 14 F270S,
254 14 V254M, V254L, V254L,
252 14 G252R,
263 14
339 15 F339del, F339S,
341 15 A341V, A341E,
258 15 H258P, H258N, H258R, H258Y,
334 15 V334A,