KCNQ1 Variant A283T Detail

We estimate the penetrance of LQTS for KCNQ1 A283T is 61%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 0 had LQTS. A283T is not present in gnomAD. A283T 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A283T around 61% (6/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.63 0.977 -1 0.852 67
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
23571586 2013 1 1 None None
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)
23571586 HEK 20 9.0 None None

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)
23571586 HEK None None None

A283T has 40 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
283 0 A283G, A283T,
284 4 E284K,
282 4 L282P,
280 6 V280A, V280E,
322 6 T322M, T322A, T322K,
324 6
325 6 G325R, G325R, G325E, G325W,
285 7
281 7 Y281C,
286 7
287 7 A287E, A287T, A287S,
279 8 F279I,
328 8 I328del,
296 8 F296S, F296L, F296L, F296L,
278 9 Y278H,
320 9 P320H, P320A, P320S,
323 9
321 9
327 10 T327A, T327S, T327S,
228 10
277 10 S277L, S277del, S277P, S277W,
295 11
276 11 S276del,
297 11 G297S, G297D, G297R,
329 11 A329T,
288 11
299 12
294 12 V294M,
319 12 V319L, V319L,
231 13 R231C, R231H, R231S,
332 13
289 14
227 14
232 14
275 14 F275del,
331 14
229 14 G229D,
330 14
144 14 T144A,
224 15 T224M,