KCNQ1 Variant D611Y Detail

We estimate the penetrance of LQTS for KCNQ1 D611Y is 29%. This variant was found in a total of 19 carriers in 6 papers or gnomAD, 7 had LQTS. D611Y is present in 1 alleles in gnomAD. D611Y has been functionally characterized in 1 papers. 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D611Y around 29% (8/29).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.31 0.184 -3 0.688 26
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
32893267 2020 2 None 2 None
30758498 2019 19 None 5 None
23153844 2012 10 None 1 None
17470695 2007 10 None 10 None
15500450 2005 11 8 3 None
12808265 2003 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 19 12 7
VARIANT FEATURES ALONE: - 10 9 1 -
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.

Functional Data Homozygously Collected

Peak current is relative to wildtype (100% being no different from wildtype). V0.5 activation is the voltages at which half of the maximal current is reached during an activation in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
15500450 Oocytes 100 0.0 None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type Peak Current IKs (%WT) V1/2 Act. Activation time (%WT) Deactivation time (%WT)
15500450 Oocytes None None None

D611Y 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
611 0 D611N, D611Y,
610 4
612 4
609 5
613 5
608 7
614 7 H614del,
607 8 A607T,
615 8
606 8
616 8
605 9
617 9
604 10
618 10
603 11
619 11 L619M,
602 11
620 11
601 12
621 12 G621S, G621C, G621D,
600 13 T600M,
622 13 G622S,
599 13
623 13
598 14 K598R,
624 14
597 14
625 14 P625R,
596 15 E596del, E596K,
626 15 G626S,