KCNQ1 Variant I198S Detail

We estimate the penetrance of LQTS for KCNQ1 I198S is 38%. We are unaware of any observations of this variant in individuals. I198S is not present in gnomAD. I198S 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I198S around 38% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.04 0.996 -1 0.938 43
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 7 3 -
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.

I198S has 57 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
198 0 I198V, I198T,
199 4 S199A,
197 5 P197L,
196 5
201 5 I201del,
243 6 R243H, R243C, R243P, R243S,
202 6 D202N, D202H,
200 7
240 7 H240R, H240P,
244 7
242 7 D242N, D242Y,
245 8 G245V,
239 8
248 8 W248C, W248C, W248R, W248R,
194 9 A194P, A194T,
115 9 E115A, E115G,
193 9 F193L, F193L, F193L,
241 9 V241F, V241I, V241G,
174 10 R174H, R174C, R174L,
171 10
203 10 L203P,
204 10 I204M, I204F,
236 10 L236Q, L236R,
246 11
205 11 V205M,
249 12 R249S, R249S,
247 12 T247I,
114 12
170 12
195 12 R195Q, R195W,
237 12
175 12 L175I,
238 12 M238V, M238L, M238L,
167 13
206 13 V206L,
111 13 Y111C,
126 13 H126D,
184 13 Y184S, Y184C, Y184D, Y184H,
267 14 Y267C,
168 14 G168R, G168R, G168R, G168R,
116 14
271 14
117 14 P117L,
178 14 A178T, A178del,
233 14 L233P,
130 14
235 14 I235N,
268 14 I268V, I268S,
172 15 V172M, V172E,
177 15 S177F,
129 15 V129I,
191 15
173 15
207 15 V207M, V207L, V207L, V207L, V207L, V207del,
192 15 R192C, R192H,
183 15 K183R,
181 15 R181C,