KCNQ1 Variant F573V Detail

We estimate the penetrance of LQTS for KCNQ1 F573V is 21%. We are unaware of any observations of this variant in individuals. F573V is not present in gnomAD. F573V 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 F573V around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.52 0.943 -1 0.854 23
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
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.

F573V 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
573 0 F573L, F573L, F573L,
572 4
574 4 I574V,
571 5 S571L, S571P,
575 5
570 7 P570L,
576 7 V576I,
569 8 K569E,
577 8
568 8 G568R, G568R, G568E,
578 8 E578K, E578V,
567 9 I567T, I567S,
579 9
566 10 S566F, S566Y, S566P,
580 10 S580G, S580N,
565 11
581 11
564 11 D564H, D564N,
582 11
563 12
583 12 R583H, R583C, R583G,
562 13 R562M, R562S, R562S,
584 13 G584S,
561 13
585 13 S585N,
560 14
586 14 N586D,
559 14 L559P,
587 14 T587M, T587R,
558 15
588 15 I588F,