KCNQ1 Variant F123S Detail

We estimate the penetrance of LQTS for KCNQ1 F123S is 84%. We are unaware of any observations of this variant in individuals. F123S is not present in gnomAD. F123S 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 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F123S around 84% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.32 0.609 0 0.861 94
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.

F123S has 26 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
123 0
124 4
120 5 W120C, W120C,
127 5 F127L, F127L, F127L,
122 6 C122Y,
126 6 H126D,
119 7 G119R, G119V,
128 8 A128del,
121 8
125 8
117 8 P117L,
118 9
129 10 V129I,
113 10
130 10
131 10
241 11 V241F, V241I, V241G,
114 12
243 13 R243H, R243C, R243P, R243S,
242 13 D242N, D242Y,
132 13 I132L,
112 14
115 14 E115A, E115G,
116 14
134 14 L134P,
133 14 V133I,