KCNQ1 Variant G584C Detail

We estimate the penetrance of LQTS for KCNQ1 G584C is 31%. We are unaware of any observations of this variant in individuals. G584C is not present in gnomAD. G584C 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 3 individuals with LQT1 and 7 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G584C around 31% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.19 1.0 -3 0.839 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0
VARIANT FEATURES ALONE: - 10 7 3 -
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.

G584C 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
584 0 G584S,
583 4 R583H, R583C, R583G,
585 4 S585N,
582 5
586 5 N586D,
581 7
587 7 T587M, T587R,
580 8 S580G, S580N,
588 8 I588F,
579 8
589 8 G589D, G589S,
578 9 E578K, E578V,
590 9 A590T,
577 10
591 10 R591H, R591C, R591L,
576 11 V576I,
592 11
575 11
593 11 N593S,
574 12 I574V,
594 12 R594Q, R594P,
573 13 F573L, F573L, F573L,
595 13 V595L, V595L,
572 13
596 13 E596del, E596K,
571 14 S571L, S571P,
597 14
570 14 P570L,
598 14 K598R,
569 15 K569E,
599 15