KCNQ1 Variant I204M Detail

We estimate the penetrance of LQTS for KCNQ1 I204M is 78%. This variant was found in a total of 3 carriers in 3 papers or gnomAD, 3 had LQTS. I204M is not present in gnomAD. I204M has been functionally characterized in 1 papers. 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I204M around 78% (10/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.2 0.982 1 0.752 83
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
32893267 2020 3 None 3 None
20421371 2010 None None None None
19716085 2009 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 3 0 3
VARIANT FEATURES ALONE: - 10 3 7 -
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
20421371 mouse ltk 34 36.1 1.159122085 0.650793651

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
20421371 mouse ltk None None None

I204M has 44 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
204 0 I204M, I204F,
205 5 V205M,
203 5 L203P,
201 5 I201del,
207 6 V207M, V207L, V207L, V207L, V207L, V207del,
200 6
208 7 A208V,
206 7 V206L,
202 7 D202N, D202H,
236 8 L236Q, L236R,
233 8 L233P,
199 9 S199A,
209 9 S209P,
232 10
240 10 H240R, H240P,
198 10 I198V, I198T,
237 10
197 10 P197L,
171 10
210 11 M210I, M210I, M210I,
211 11
194 11 A194P, A194T,
239 11
229 11 G229D,
164 12
167 12
168 12 G168R, G168R, G168R, G168R,
212 12
230 12
235 13 I235N,
196 13
234 13 Q234H, Q234H,
225 14 S225L, S225del,
195 14 R195Q, R195W,
213 14
275 14 F275del,
243 15 R243H, R243C, R243P, R243S,
193 15 F193L, F193L, F193L,
170 15
174 15 R174H, R174C, R174L,
238 15 M238V, M238L, M238L,
160 15 E160del, E160K, E160V,
226 15 A226V,
175 15 L175I,