KCNQ1 Variant Q604L Detail

We estimate the penetrance of LQTS for KCNQ1 Q604L is 26%. We are unaware of any observations of this variant in individuals. Q604L is not present in gnomAD. Q604L 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 2 individuals with LQT1 and 8 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Q604L around 26% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.09 0.027 -3 0.642 32
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 8 2 -
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.

Q604L 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
604 0
603 4
605 4
602 5
606 5
601 7
607 7 A607T,
600 8 T600M,
608 8
599 8
609 8
598 9 K598R,
610 9
597 10
611 10 D611N, D611Y,
596 11 E596del, E596K,
612 11
595 11 V595L, V595L,
613 11
594 12 R594Q, R594P,
614 12 H614del,
593 13 N593S,
615 13
592 13
616 13
591 14 R591H, R591C, R591L,
617 14
590 14 A590T,
618 14
589 15 G589D, G589S,
619 15 L619M,