KCNQ1 Variant C214S Detail

We estimate the penetrance of LQTS for KCNQ1 C214S is 19%. We are unaware of any observations of this variant in individuals. C214S is not present in gnomAD. C214S has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 C214S around 19% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.82 0.126 -1 0.62 22
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 9 1 -
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.

C214S has 35 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
214 0 C214Y,
215 5 V215M, V215G, V215L, V215L,
213 5
211 5
216 6 G216R,
210 6 M210I, M210I, M210I,
212 6
209 8 S209P,
221 9
161 9
217 9
208 9 A208V,
219 10 G219E,
222 10
157 10 F157C,
207 10 V207M, V207L, V207L, V207L, V207L, V207del,
226 10 A226V,
218 11
164 11
225 11 S225L, S225del,
160 12 E160del, E160K, E160V,
206 12 V206L,
230 12
220 12 Q220K,
165 12 V165M,
223 13
162 13 V162M,
224 14 T224M,
229 14 G229D,
205 14 V205M,
233 14 L233P,
227 14
158 15
163 15
156 15