KCNQ1 Variant G345R Detail

We estimate the penetrance of LQTS for KCNQ1 G345R is 84%. This variant was found in a total of 2 carriers in 4 papers or gnomAD, 2 had LQTS. G345R is not present in gnomAD. G345R 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 8 individuals with LQT1 and 2 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G345R around 84% (10/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.36 1.0 -2 0.892 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 1 None 1 None
26496715 2016 1 None 1 None
14678125 2003 12 None 12 None
10220144 1999 5 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.

G345R has 20 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
345 5 G345R, G345R, G345A,
344 8 A344V, A344E,
348 8
349 8 S349W,
346 9
342 9 L342F, L342P,
341 9 A341V, A341E,
347 10 L347P, L347R,
343 10 P343S, P343L, P343R,
350 11 G350V, G350R, G350R, G350W,
352 11
338 12 S338F,
351 12 F351L, F351L, F351L, F351S,
353 13 L353P,
258 14 H258P, H258N, H258R, H258Y,
262 14 L262P, L262R, L262V,
337 14
339 14 F339del, F339S,
340 15 F340del, F340L, F340L, F340L, F340S,
265 15 T265I,