KCNQ1 Variant A341E Detail

We estimate the penetrance of LQTS for KCNQ1 A341E is 77%. This variant was found in a total of 4 carriers in 13 papers or gnomAD, 3 had LQTS. A341E is not present in gnomAD. A341E 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 A341E around 77% (10/14).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.68 1.0 -3 0.95 85
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
34135346 2021 1 1 None None
32893267 2020 1 None 1 None
30758498 2019 1 None None None
24217263 2013 1 None 1 None
23631430 2013 2 None None None
23153844 2012 11 None 1 None
22949429 2012 1 None 1 None
22677073 2012 1 None None SUDS
19841300 2009 1 None 1 None
19716085 2009 4 None 4 None
19490272 2009 10 None 10 None
17470695 2007 9 None 9 None
14678125 2003 7 None 7 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)
10376919 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)
10376919 Oocytes 40 6.0 1.0 None

A341E has 21 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
344 7 A344V, A344E,
341 7 A341V, A341E,
345 9 G345R, G345R, G345A,
343 10 P343S, P343L, P343R,
342 11 L342F, L342P,
348 11
312 11 T312del, T312I,
347 11 L347P, L347R,
338 11 S338F,
337 12
346 12
340 12 F340del, F340L, F340L, F340L, F340S,
311 12 T311A, T311I,
349 13 S349W,
351 14 F351L, F351L, F351L, F351S,
310 14 V310I,
339 14 F339del, F339S,
313 14
336 15 A336S,
350 15 G350V, G350R, G350R, G350W,
262 15 L262P, L262R, L262V,