KCNQ1 Variant D649V Detail

We estimate the penetrance of LQTS for KCNQ1 D649V is 10%. We are unaware of any observations of this variant in individuals. D649V is not present in gnomAD. D649V has not been functionally characterized. This residue is located in a Non_Hotspot region for LQT1. In silico predictions, functional data (if available), and location in structure are equivalent to observing 0 individuals with LQT1 and 10 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D649V around 10% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.39 0.0 -1 0.515 0
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 10 0 -
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.

D649V 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
649 0 D649N, D649G,
648 4 V648I,
650 4
647 5
651 5
646 7
652 7
645 8
653 8 F653Y,
644 8
654 8
643 9 G643S,
655 9
642 10
656 10
641 11 P641L,
657 11 N657S,
640 11 Q640L,
658 11 T658N,
639 12
659 12
638 13
660 13 P660S,
637 13
661 13
636 14
662 14
635 14 G635R, G635R,
663 14 E663K,
634 15
664 15