KCNQ1 Variant K326E Detail

We estimate the penetrance of LQTS for KCNQ1 K326E is 30%. We are unaware of any observations of this variant in individuals. K326E is not present in gnomAD. K326E has not been functionally characterized. This residue is located in a Mild_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K326E around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.4 0.995 -2 0.94 33
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 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 8 2 -
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.

K326E has 29 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
327 6 T327A, T327S, T327S,
324 6
323 7
330 8
304 9 W304R, W304R,
331 10
305 11 W305S, W305L, W305C, W305C, W305R, W305R,
318 11
301 11
302 12 A302V, A302E, A302T,
306 12 G306V, G306R, G306R,
300 12 A300T, A300S,
307 12 V307L, V307L,
303 13 L303P,
296 13 F296S, F296L, F296L, F296L,
295 13
320 13 P320H, P320A, P320S,
309 13 T309I, T309R,
298 14 S298I, S298N,
280 14 V280A, V280E,
141 14 V141M,
145 14
277 14 S277L, S277del, S277P, S277W,
315 14 Y315C, Y315S, Y315N, Y315H, Y315F,
334 14 V334A,
326 14
284 15 E284K,
297 15 G297S, G297D, G297R,
299 15