KCNQ1 Variant T312I Detail

We estimate the penetrance of LQTS for KCNQ1 T312I is 84%. This variant was found in a total of 3 carriers in 12 papers or gnomAD, 3 had LQTS. T312I is not present in gnomAD. T312I has been functionally characterized in 3 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T312I around 84% (10/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.54 1.0 1 0.982 92
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
27114410 2016 1 None None None
23631430 2013 3 None None None
23153844 2012 17 None 1 None
22949429 2012 1 None 1 None
22677073 2012 1 None None SUDS
19841300 2009 1 None 1 None
19716085 2009 2 None 2 None
19490272 2009 17 None 17 None
17470695 2007 14 None 14 None
17192539 2006 1 None 1 None
14678125 2003 13 None 13 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)
22456477 HEK None None None
15051636 Oocytes 10 None None None
9323054 Oocytes None 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)
22456477 HEK 30 None None None
15051636 Oocytes None None None
9323054 Oocytes 25 14.0 1.0 None

T312I has 22 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 5 T312del, T312I,
313 8
314 8 G314S, G314D, G314C, G314del,
337 9
311 9 T311A, T311I,
309 10 T309I, T309R,
310 10 V310I,
308 11 V308F,
341 11 A341V, A341E,
333 11
315 12 Y315C, Y315S, Y315N, Y315H, Y315F,
334 12 V334A,
338 12 S338F,
340 13 F340del, F340L, F340L, F340L, F340S,
336 13 A336S,
307 14 V307L, V307L,
316 14 G316E, G316R, G316R, G316V,
306 14 G306V, G306R, G306R,
305 14 W305S, W305L, W305C, W305C, W305R, W305R,
330 14
344 15 A344V, A344E,
329 15 A329T,