KCNQ1 Variant A300T Detail

We estimate the penetrance of LQTS for KCNQ1 A300T is 24%. This variant was found in a total of 14 carriers in 7 papers or gnomAD, 2 had LQTS. A300T is present in 12 alleles in gnomAD. A300T has been functionally characterized in 2 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A300T around 24% (5/24).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.89 1.0 0 0.907 33
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
32893267 2020 2 None 2 None
29197658 2018 1 None 1 None
24667783 2015 None None None None
23631430 2013 1 None None None
22949429 2012 1 1 None None
19841300 2009 1 1 None None
14678125 2003 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 14 12 2
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.

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)
11087258 Oocytes 15 -19.0 None None
30571187 HEK 23 -14.3 None 0.915525397

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)
11087258 Oocytes 50 -10.0 None None
30571187 HEK None None None

A300T has 46 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
300 0 A300T, A300S,
301 4
298 4 S298I, S298N,
303 5 L303P,
299 5
302 5 A302V, A302E, A302T,
141 7 V141M,
304 7 W304R, W304R,
297 8 G297S, G297D, G297R,
145 8
144 8 T144A,
281 8 Y281C,
277 9 S277L, S277del, S277P, S277W,
323 9
142 9
327 10 T327A, T327S, T327S,
140 10 S140G, S140R, S140R, S140R,
307 11 V307L, V307L,
138 11
274 11 I274V,
143 11 S143F, S143P, S143Y,
273 11 L273F, L273V, L273R,
231 12 R231C, R231H, R231S,
137 12 L137F, L137P,
294 12 V294M,
148 12
278 12 Y278H,
285 12
147 13 Q147R,
326 13
146 13 E146K, E146G, E146Q,
293 14 R293C, R293H,
139 14
320 14 P320H, P320A, P320S,
235 14 I235N,
325 14 G325R, G325R, G325E, G325W,
331 14
275 14 F275del,
322 15 T322M, T322A, T322K,
329 15 A329T,
270 15 F270S,
234 15 Q234H, Q234H,
319 15 V319L, V319L,
310 15 V310I,
272 15 G272D, G272S, G272V,
321 15