KCNQ1 Variant F139C Detail

We estimate the penetrance of LQTS for KCNQ1 F139C is 49%. We are unaware of any observations of this variant in individuals. F139C is not present in gnomAD. F139C 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F139C around 49% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.29 0.996 0 0.778 51
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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 6 4 -
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.

F139C has 47 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
139 0
138 5
135 5
136 5
142 6
140 6 S140G, S140R, S140R, S140R,
156 6
152 7
137 7 L137F, L137P,
141 7 V141M,
155 7
143 7 S143F, S143P, S143Y,
159 8 M159del,
148 9
134 9 L134P,
234 10 Q234H, Q234H,
133 10 V133I,
132 10 I132L,
160 10 E160del, E160K, E160V,
151 10
149 10
153 10 T153M,
154 10
144 10 T144A,
145 10
231 11 R231C, R231H, R231S,
131 12
158 12
163 12
150 12 A150T,
230 12
299 12
147 13 Q147R,
237 13
157 13 F157C,
235 13 I235N,
300 14 A300T, A300S,
130 14
162 14 V162M,
238 14 M238V, M238L, M238L,
146 14 E146K, E146G, E146Q,
161 14
129 15 V129I,
233 15 L233P,
298 15 S298I, S298N,
303 15 L303P,
128 15 A128del,