KCNQ1 Variant A223V Detail

We estimate the penetrance of LQTS for KCNQ1 A223V is 43%. We are unaware of any observations of this variant in individuals. A223V is not present in gnomAD. A223V 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 A223V around 43% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.82 0.995 1 0.846 46
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.

A223V has 31 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
223 0
224 4 T224M,
222 4
227 5
219 6 G219E,
221 6
220 6 Q220K,
225 6 S225L, S225del,
226 6 A226V,
228 8
215 9 V215M, V215G, V215L, V215L,
217 9
216 9 G216R,
212 9
218 9
229 10 G229D,
230 11
231 12 R231C, R231H, R231S,
213 12
211 12
285 13
214 13 C214Y,
153 13 T153M,
282 14 L282P,
286 14
157 14 F157C,
208 14 A208V,
209 14 S209P,
144 14 T144A,
143 14 S143F, S143P, S143Y,
233 15 L233P,