KCNQ1 Variant I132L Detail

We estimate the penetrance of LQTS for KCNQ1 I132L is 15%. This variant was found in a total of 2 carriers in 0 papers or gnomAD, 0 had LQTS. I132L is present in 2 alleles in gnomAD. I132L 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 I132L around 15% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.25 0.009 4 0.623 23
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: - 2 2 0
VARIANT FEATURES ALONE: - 10 9 1 -
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 112 2.1 None 1.70306301

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

I132L has 43 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
132 0 I132L,
133 5 V133I,
129 5 V129I,
131 5
135 6
128 6 A128del,
134 7 L134P,
136 7
130 7
163 7
159 8 M159del,
127 9 F127L, F127L, F127L,
137 9 L137F, L137P,
166 9 F166V,
167 9
237 9
139 10
125 10
138 10
162 11 V162M,
160 11 E160del, E160K, E160V,
126 11 H126D,
234 11 Q234H, Q234H,
238 11 M238V, M238L, M238L,
241 11 V241F, V241I, V241G,
156 12
240 12 H240R, H240P,
124 12
164 12
158 12
170 13
140 13 S140G, S140R, S140R, S140R,
155 13
165 13 V165M,
123 13
235 14 I235N,
161 14
239 14
233 14 L233P,
236 14 L236Q, L236R,
168 15 G168R, G168R, G168R, G168R,
205 15 V205M,
230 15