KCNQ1 Variant K569E Detail

We estimate the penetrance of LQTS for KCNQ1 K569E is 81%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. K569E is not present in gnomAD. K569E 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 K569E around 81% (8/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.51 0.994 0 0.915 89
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
19716085 2009 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.

K569E has 31 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
569 0 K569E,
568 4 G568R, G568R, G568E,
570 4 P570L,
567 5 I567T, I567S,
571 5 S571L, S571P,
566 7 S566F, S566Y, S566P,
572 7
565 8
573 8 F573L, F573L, F573L,
564 8 D564H, D564N,
574 8 I574V,
563 9
575 9
562 10 R562M, R562S, R562S,
576 10 V576I,
561 11
577 11
560 11
578 11 E578K, E578V,
559 12 L559P,
579 12
558 13
580 13 S580G, S580N,
557 13 K557E,
581 13
556 14
582 14
555 14 R555H, R555C, R555S, R555L,
583 14 R583H, R583C, R583G,
554 15
584 15 G584S,