KCNQ1 Variant S217T Detail

We estimate the penetrance of LQTS for KCNQ1 S217T is 66%. We are unaware of any observations of this variant in individuals. S217T is not present in gnomAD. S217T 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S217T around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.06 0.624 0 0.795 69
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 4 6 -
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.

S217T has 37 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
217 0
216 4 G216R,
218 4
222 5
219 7 G219E,
157 7 F157C,
215 7 V215M, V215G, V215L, V215L,
213 8
153 8 T153M,
226 9 A226V,
223 9
214 9 C214Y,
212 9
154 9
221 10
227 10
220 11 Q220K,
225 11 S225L, S225del,
161 11
156 11
230 12
224 12 T224M,
160 12 E160del, E160K, E160V,
211 12
152 12
155 13
149 13
209 13 S209P,
150 13 A150T,
158 14
229 14 G229D,
143 14 S143F, S143P, S143Y,
210 14 M210I, M210I, M210I,
228 14
231 15 R231C, R231H, R231S,
159 15 M159del,
151 15