KCNQ1 Variant T311I Detail

We estimate the penetrance of LQTS for KCNQ1 T311I is 67%. This variant was found in a total of 1 carriers in 3 papers or gnomAD, 0 had LQTS. T311I is present in 1 alleles in gnomAD. T311I 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 T311I around 67% (7/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.7 1.0 -2 0.956 77
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
20368164 2009 None None None None
17192539 2006 1 None 1 None
14678125 2003 2 None 2 None
LITERATURE, COHORT, AND GNOMAD: - 1 1 0
VARIANT FEATURES ALONE: - 10 3 7 -
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.

T311I has 35 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
311 6 T311A, T311I,
312 6 T312del, T312I,
310 8 V310I,
313 8
337 9
309 9 T309I, T309R,
308 9 V308F,
314 10 G314S, G314D, G314C, G314del,
340 10 F340del, F340L, F340L, F340L, F340S,
307 11 V307L, V307L,
333 11
341 11 A341V, A341E,
336 11 A336S,
306 12 G306V, G306R, G306R,
315 12 Y315C, Y315S, Y315N, Y315H, Y315F,
338 12 S338F,
334 12 V334A,
305 13 W305S, W305L, W305C, W305C, W305R, W305R,
273 13 L273F, L273V, L273R,
332 13
329 13 A329T,
276 13 S276del,
330 13
272 14 G272D, G272S, G272V,
304 14 W304R, W304R,
339 14 F339del, F339S,
269 14 G269D, G269S, G269del,
335 14 F335L, F335L, F335L,
270 14 F270S,
316 14 G316E, G316R, G316R, G316V,
344 14 A344V, A344E,
277 14 S277L, S277del, S277P, S277W,
343 15 P343S, P343L, P343R,
342 15 L342F, L342P,
303 15 L303P,