KCNQ1 Variant T309R Detail

We estimate the penetrance of LQTS for KCNQ1 T309R is 78%. This variant was found in a total of 1 carriers in 2 papers or gnomAD, 1 had LQTS. T309R is not present in gnomAD. T309R 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T309R around 78% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.6 1.0 -3 0.912 84
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 1 None 1 None
17192539 2006 1 None 1 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.

T309R has 30 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
312 10 T312del, T312I,
309 10 T309I, T309R,
314 10 G314S, G314D, G314C, G314del,
330 11
313 11
337 12
333 12
308 12 V308F,
311 12 T311A, T311I,
310 12 V310I,
329 13 A329T,
315 13 Y315C, Y315S, Y315N, Y315H, Y315F,
316 13 G316E, G316R, G316R, G316V,
305 13 W305S, W305L, W305C, W305C, W305R, W305R,
326 13
334 13 V334A,
303 14 L303P,
279 14 F279I,
331 14
306 14 G306V, G306R, G306R,
319 14 V319L, V319L,
320 14 P320H, P320A, P320S,
275 14 F275del,
270 14 F270S,
336 15 A336S,
307 15 V307L, V307L,
327 15 T327A, T327S, T327S,
271 15
328 15 I328del,
325 15 G325R, G325R, G325E, G325W,