KCNQ1 Variant I145L Detail

We estimate the penetrance of LQTS for KCNQ1 I145L is 35%. We are unaware of any observations of this variant in individuals. I145L is not present in gnomAD. I145L 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I145L around 35% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.8 0.573 1 0.717 40
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 7 3 -
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.

I145L 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
145 0
144 5 T144A,
142 5
148 5
143 6 S143F, S143P, S143Y,
147 6 Q147R,
141 6 V141M,
146 6 E146K, E146G, E146Q,
298 6 S298I, S298N,
149 8
300 8 A300T, A300S,
297 8 G297S, G297D, G297R,
140 9 S140G, S140R, S140R, S140R,
299 9
301 10
152 10
139 10
138 10
150 11 A150T,
281 11 Y281C,
231 11 R231C, R231H, R231S,
323 11
151 12
303 12 L303P,
153 12 T153M,
302 12 A302V, A302E, A302T,
285 13
137 13 L137F, L137P,
296 13 F296S, F296L, F296L, F296L,
294 13 V294M,
156 13
136 14
227 14
155 14
326 14
304 15 W304R, W304R,
135 15
234 15 Q234H, Q234H,
277 15 S277L, S277del, S277P, S277W,
154 15
327 15 T327A, T327S, T327S,