KCNQ1 Variant T144A Detail

We estimate the penetrance of LQTS for KCNQ1 T144A is 60%. This variant was found in a total of 1 carriers in 4 papers or gnomAD, 1 had LQTS. T144A is not present in gnomAD. T144A 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T144A around 60% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.5 0.998 -2 0.904 64
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
19716085 2009 1 None 1 None
17470695 2007 7 None 7 None
17224687 2007 2 1 1 None
14678125 2003 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
VARIANT FEATURES ALONE: - 10 5 5 -
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 50 -8.6 None 0.958145945

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

T144A has 58 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
144 0 T144A,
143 4 S143F, S143P, S143Y,
145 5
141 5 V141M,
298 6 S298I, S298N,
140 6 S140G, S140R, S140R, S140R,
142 7
299 7
231 7 R231C, R231H, R231S,
146 7 E146K, E146G, E146Q,
297 8 G297S, G297D, G297R,
281 8 Y281C,
300 8 A300T, A300S,
149 8
148 9
285 9
227 10
147 10 Q147R,
301 10
152 10
139 10
138 11
302 11 A302V, A302E, A302T,
153 11 T153M,
303 11 L303P,
228 11
137 11 L137F, L137P,
156 11
230 12
296 12 F296S, F296L, F296L, F296L,
234 12 Q234H, Q234H,
150 12 A150T,
278 12 Y278H,
282 12 L282P,
136 12
226 12 A226V,
229 12 G229D,
277 12 S277L, S277del, S277P, S277W,
294 13 V294M,
286 13
151 13
280 13 V280A, V280E,
235 14 I235N,
155 14
284 14 E284K,
154 14
222 14
283 14 A283G, A283T,
232 14
274 14 I274V,
225 14 S225L, S225del,
135 14
223 14
323 15
160 15 E160del, E160K, E160V,
287 15 A287E, A287T, A287S,
295 15
233 15 L233P,