KCNQ1 Variant F222C Detail

We estimate the penetrance of LQTS for KCNQ1 F222C is 56%. We are unaware of any observations of this variant in individuals. F222C is not present in gnomAD. F222C 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 F222C around 56% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.6 1.0 -2 0.897 61
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 5 5 -
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.

F222C has 39 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
222 0
223 4
226 4 A226V,
219 5 G219E,
217 5
216 5 G216R,
227 6
221 6
215 6 V215M, V215G, V215L, V215L,
225 6 S225L, S225del,
212 7
224 7 T224M,
218 7
213 8
220 8 Q220K,
230 9
228 9
157 9 F157C,
229 10 G229D,
214 10 C214Y,
211 10
153 10 T153M,
231 11 R231C, R231H, R231S,
209 11 S209P,
160 12 E160del, E160K, E160V,
156 12
208 12 A208V,
154 12
143 13 S143F, S143P, S143Y,
161 13
210 13 M210I, M210I, M210I,
233 13 L233P,
152 14
149 14
144 14 T144A,
140 14 S140G, S140R, S140R, S140R,
234 14 Q234H, Q234H,
232 15
155 15