KCNQ1 Variant D582V Detail

We estimate the penetrance of LQTS for KCNQ1 D582V is 44%. We are unaware of any observations of this variant in individuals. D582V is not present in gnomAD. D582V 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 4 individuals with LQT1 and 6 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D582V around 44% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.88 0.599 -1 0.845 47
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.

D582V 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
582 0
581 4
583 4 R583H, R583C, R583G,
580 5 S580G, S580N,
584 5 G584S,
579 7
585 7 S585N,
578 8 E578K, E578V,
586 8 N586D,
577 8
587 8 T587M, T587R,
576 9 V576I,
588 9 I588F,
575 10
589 10 G589D, G589S,
574 11 I574V,
590 11 A590T,
573 11 F573L, F573L, F573L,
591 11 R591H, R591C, R591L,
572 12
592 12
571 13 S571L, S571P,
593 13 N593S,
570 13 P570L,
594 13 R594Q, R594P,
569 14 K569E,
595 14 V595L, V595L,
568 14 G568R, G568R, G568E,
596 14 E596del, E596K,
567 15 I567T, I567S,
597 15