KCNQ1 Variant M210I Detail

We estimate the penetrance of LQTS for KCNQ1 M210I is 17%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. M210I is present in 1 alleles in gnomAD. M210I has been functionally characterized in 1 papers. 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 M210I around 17% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
0.11 0.004 3 0.488 14
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
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)
30571187 HEK 63 -1.2 None 0.53210011

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)
30571187 HEK None None None

M210I has 40 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
210 0 M210I, M210I, M210I,
211 5
207 5 V207M, V207L, V207L, V207L, V207L, V207del,
209 5 S209P,
214 6 C214Y,
208 6 A208V,
206 6 V206L,
213 7
212 7
164 8
161 9
205 9 V205M,
215 9 V215M, V215G, V215L, V215L,
165 10 V165M,
203 10 L203P,
216 10 G216R,
168 11 G168R, G168R, G168R, G168R,
204 11 I204M, I204F,
160 11 E160del, E160K, E160V,
221 11
233 11 L233P,
230 12
226 12 A226V,
167 12
225 12 S225L, S225del,
162 13 V162M,
157 13 F157C,
163 13
229 13 G229D,
222 13
237 13
171 13
202 13 D202N, D202H,
169 13 T169M, T169R,
217 14
219 14 G219E,
166 14 F166V,
234 15 Q234H, Q234H,
172 15 V172M, V172E,
201 15 I201del,