KCNQ1 Variant I200M Detail

We estimate the penetrance of LQTS for KCNQ1 I200M is 55%. We are unaware of any observations of this variant in individuals. I200M is not present in gnomAD. I200M 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 I200M around 55% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.39 0.879 0 0.814 64
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.

I200M has 41 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
200 0
199 4 S199A,
201 5 I201del,
197 5 P197L,
194 6 A194P, A194T,
203 6 L203P,
204 6 I204M, I204F,
198 7 I198V, I198T,
202 7 D202N, D202H,
196 7
195 8 R195Q, R195W,
171 9
205 10 V205M,
193 10 F193L, F193L, F193L,
240 10 H240R, H240P,
206 11 V206L,
207 11 V207M, V207L, V207L, V207L, V207L, V207del,
191 11
236 11 L236Q, L236R,
239 12
243 12 R243H, R243C, R243P, R243S,
175 12 L175I,
174 12 R174H, R174C, R174L,
208 13 A208V,
244 13
192 13 R192C, R192H,
248 13 W248C, W248C, W248R, W248R,
245 13 G245V,
233 14 L233P,
168 14 G168R, G168R, G168R, G168R,
242 14 D242N, D242Y,
237 14
115 14 E115A, E115G,
189 14 G189R, G189R, G189E,
184 14 Y184S, Y184C, Y184D, Y184H,
167 14
190 14 R190W, R190Q, R190L,
172 14 V172M, V172E,
170 14
209 14 S209P,
232 15