KCNQ1 Variant I588F Detail

We estimate the penetrance of LQTS for KCNQ1 I588F is 51%. This variant was found in a total of 2 carriers in 2 papers or gnomAD, 1 had LQTS. I588F is not present in gnomAD. I588F 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 5 individuals with LQT1 and 5 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I588F around 51% (6/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.94 0.992 -1 0.76 52
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
33614747 2021 1 None 1 None
27041150 2016 2 1 None None
LITERATURE, COHORT, AND GNOMAD: - 2 1 1
VARIANT FEATURES ALONE: - 10 5 5 -
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.

I588F 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
588 0 I588F,
587 4 T587M, T587R,
589 4 G589D, G589S,
586 5 N586D,
590 5 A590T,
585 7 S585N,
591 7 R591H, R591C, R591L,
584 8 G584S,
592 8
583 8 R583H, R583C, R583G,
593 8 N593S,
582 9
594 9 R594Q, R594P,
581 10
595 10 V595L, V595L,
580 11 S580G, S580N,
596 11 E596del, E596K,
579 11
597 11
578 12 E578K, E578V,
598 12 K598R,
577 13
599 13
576 13 V576I,
600 13 T600M,
575 14
601 14
574 14 I574V,
602 14
573 15 F573L, F573L, F573L,
603 15