KCNQ1 Variant R594Q Detail

We estimate the penetrance of LQTS for KCNQ1 R594Q is 75%. This variant was found in a total of 34 carriers in 21 papers or gnomAD, 26 had LQTS. R594Q is present in 7 alleles in gnomAD. R594Q has been functionally characterized in 1 papers. 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 6 individuals with LQT1 and 4 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R594Q around 75% (32/44).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.41 0.999 1 0.846 72
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
34135346 2021 1 None 1 None
33777698 2021 2 None 2 None
32893267 2020 11 None 11 None
30974404 2019 2 1 1 None
30758498 2019 6 None None None
29677589 2018 None None None None
27041096 2016 4 None 4 None
26496715 2016 1 None 1 None
26481773 2015 None None None None
24218437 2013 3 None 3 None
23631430 2013 4 None None None
23153844 2012 14 None 1 None
22949429 2012 3 None 3 None
22885918 2012 1 None 1 None
21956039 2011 1 None 1 None
19841300 2009 3 None 3 None
19716085 2009 15 None 15 None
17470695 2007 11 None 11 None
16818214 2006 1 None 1 None
14678125 2003 3 None 3 None
11140949 2000 1 None 1 None
LITERATURE, COHORT, AND GNOMAD: - 34 8 26
VARIANT FEATURES ALONE: - 10 4 6 -
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)
15051636 Oocytes 5 60.0 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)
15051636 Oocytes 70 0.0 None None

R594Q 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
594 0 R594Q, R594P,
593 4 N593S,
595 4 V595L, V595L,
592 5
596 5 E596del, E596K,
591 7 R591H, R591C, R591L,
597 7
590 8 A590T,
598 8 K598R,
589 8 G589D, G589S,
599 8
588 9 I588F,
600 9 T600M,
587 10 T587M, T587R,
601 10
586 11 N586D,
602 11
585 11 S585N,
603 11
584 12 G584S,
604 12
583 13 R583H, R583C, R583G,
605 13
582 13
606 13
581 14
607 14 A607T,
580 14 S580G, S580N,
608 14
579 15
609 15