KCNQ1 Variant G325E Detail

We estimate the penetrance of LQTS for KCNQ1 G325E is 81%. This variant was found in a total of 1 carriers in 2 papers or gnomAD, 1 had LQTS. G325E is not present in gnomAD. G325E 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 7 individuals with LQT1 and 3 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G325E around 81% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.52 1.0 3 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
30758498 2019 2 None 2 None
21956039 2011 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 1 0 1
VARIANT FEATURES ALONE: - 10 3 7 -
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.

G325E has 40 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
325 0 G325R, G325R, G325E, G325W,
324 4
328 4 I328del,
322 5 T322M, T322A, T322K,
327 5 T327A, T327S, T327S,
320 6 P320H, P320A, P320S,
329 6 A329T,
283 6 A283G, A283T,
284 7 E284K,
323 7
321 8
330 8
279 8 F279I,
282 9 L282P,
331 9
332 10
287 11 A287E, A287T, A287S,
333 11
278 11 Y278H,
304 11 W304R, W304R,
285 12
286 12
305 13 W305S, W305L, W305C, W305C, W305R, W305R,
308 13 V308F,
301 13
307 13 V307L, V307L,
318 14
302 14 A302V, A302E, A302T,
300 14 A300T, A300S,
306 14 G306V, G306R, G306R,
288 14
303 14 L303P,
326 14
334 14 V334A,
275 14 F275del,
289 14
317 14 D317N, D317G, D317Y,
272 15 G272D, G272S, G272V,
335 15 F335L, F335L, F335L,
296 15 F296S, F296L, F296L, F296L,