KCNQ1 Variant A344V Detail

We estimate the penetrance of LQTS for KCNQ1 A344V is 82%. This variant was found in a total of 20 carriers in 11 papers or gnomAD, 17 had LQTS. A344V is not present in gnomAD. A344V has been functionally characterized in 2 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 A344V around 82% (24/30).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.59 1.0 4 0.908 88
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 7 None 7 None
30758498 2019 1 None 1 None
28944242 2017 2 2 None None
24217263 2013 3 None 3 None
23631430 2013 2 None None None
19716085 2009 1 None 1 None
19490272 2009 18 None 18 None
17470695 2007 17 None 17 None
17192539 2006 4 None 4 None
16931984 2006 None None None None
16922724 2006 1 1 None bradycardia
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)
16931984 CHO 100 40.0 None None
30571187 HEK 19 18.8 None 2.432034119

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)
16931984 CHO None None None
30571187 HEK None None None

A344V has 23 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,
345 7 G345R, G345R, G345A,
341 9 A341V, A341E,
342 10 L342F, L342P,
348 10
343 10 P343S, P343L, P343R,
346 11
349 11 S349W,
338 11 S338F,
347 11 L347P, L347R,
337 13
255 14
350 14 G350V, G350R, G350R, G350W,
340 14 F340del, F340L, F340L, F340L, F340S,
339 14 F339del, F339S,
351 14 F351L, F351L, F351L, F351S,
352 14
264 14
251 14 L251P, L251Q,
312 14 T312del, T312I,
263 15
268 15 I268V, I268S,
262 15 L262P, L262R, L262V,