KCNQ1 Variant V334A Detail

We estimate the penetrance of LQTS for KCNQ1 V334A is 67%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. V334A is not present in gnomAD. V334A 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V334A around 67% (7/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.3 0.89 -2 0.931 70
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
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.

V334A has 26 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
270 11 F270S,
269 11 G269D, G269S, G269del,
339 11 F339del, F339S,
266 11 L266P,
273 12 L273F, L273V, L273R,
327 12 T327A, T327S, T327S,
306 12 G306V, G306R, G306R,
265 13 T265I,
272 13 G272D, G272S, G272V,
312 13 T312del, T312I,
336 13 A336S,
311 14 T311A, T311I,
255 14
325 14 G325R, G325R, G325E, G325W,
268 14 I268V, I268S,
332 14
334 14 V334A,
313 14
326 14
333 14
341 14 A341V, A341E,
262 15 L262P, L262R, L262V,
276 15 S276del,
344 15 A344V, A344E,
271 15
274 15 I274V,