KCNQ1 Variant T327A Detail

We estimate the penetrance of LQTS for KCNQ1 T327A is 21%. This variant was found in a total of 1 carriers in 0 papers or gnomAD, 0 had LQTS. T327A is present in 1 alleles in gnomAD. T327A has not been functionally characterized. 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T327A around 21% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.43 0.13 -2 0.653 27
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: - 1 1 0
VARIANT FEATURES ALONE: - 10 8 2 -
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.

T327A has 34 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
327 0 T327A, T327S, T327S,
328 5 I328del,
325 5 G325R, G325R, G325E, G325W,
324 5
330 6
326 6
329 6 A329T,
331 6
323 6
322 8 T322M, T322A, T322K,
332 9
279 10 F279I,
283 10 A283G, A283T,
284 11 E284K,
334 12 V334A,
321 12
282 12 L282P,
335 13 F335L, F335L, F335L,
141 13 V141M,
138 13
280 14 V280A, V280E,
306 14 G306V, G306R, G306R,
276 14 S276del,
277 14 S277L, S277del, S277P, S277W,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
320 14 P320H, P320A, P320S,
302 14 A302V, A302E, A302T,
309 14 T309I, T309R,
142 15
333 15
307 15 V307L, V307L,
303 15 L303P,
145 15
304 15 W304R, W304R,