KCNQ1 Variant I567T Detail

We estimate the penetrance of LQTS for KCNQ1 I567T is 74%. This variant was found in a total of 18 carriers in 8 papers or gnomAD, 12 had LQTS. I567T is not present in gnomAD. I567T 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 I567T around 74% (20/28).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.0 0.706 0 0.821 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 4 None 4 None
31424047 2019 2 1 1 None
30758498 2019 1 None 1 None
27041096 2016 2 None 2 None
24372464 2015 5 5 None None
22429796 2012 5 0 5 None
19716085 2009 3 None 3 None
17192539 2006 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 18 6 12
VARIANT FEATURES ALONE: - 10 2 8 -
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.

I567T has 7 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
567 8 I567T, I567S,
566 8 S566F, S566Y, S566P,
563 10
562 11 R562M, R562S, R562S,
565 13
564 13 D564H, D564N,
559 14 L559P,