KCNQ1 Variant T169M Detail

We estimate the penetrance of LQTS for KCNQ1 T169M is 9%. This variant was found in a total of 12 carriers in 0 papers or gnomAD, 0 had LQTS. T169M is present in 12 alleles in gnomAD. T169M 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 T169M around 9% (1/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.5 0.501 1 0.507 12
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 65 -0.1 None 0.0

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

T169M has 36 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
169 0 T169M, T169R,
168 4 G168R, G168R, G168R, G168R,
170 5
172 5 V172M, V172E,
166 6 F166V,
165 6 V165M,
173 6
167 7
171 8
164 9
174 9 R174H, R174C, R174L,
176 9
175 10 L175I,
206 10 V206L,
163 10
162 11 V162M,
114 11
202 12 D202N, D202H,
125 12
203 12 L203P,
177 13 S177F,
110 13 V110I,
161 13
129 13 V129I,
210 13 M210I, M210I, M210I,
113 13
205 13 V205M,
207 14 V207M, V207L, V207L, V207L, V207L, V207del,
240 14 H240R, H240P,
209 14 S209P,
199 14 S199A,
126 14 H126D,
237 14
107 14 Q107H, Q107H,
115 14 E115A, E115G,
160 15 E160del, E160K, E160V,