KCNQ1 Variant T600M Detail

We estimate the penetrance of LQTS for KCNQ1 T600M is 9%. This variant was found in a total of 50 carriers in 3 papers or gnomAD, 3 had LQTS. T600M is present in 47 alleles in gnomAD. T600M 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 T600M around 9% (5/60).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.27 0.81 0 0.716 25
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
29197658 2018 3 None 3 None
23631430 2013 1 None None None
19716085 2009 3 None 3 None
LITERATURE, COHORT, AND GNOMAD: - 50 47 3
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.

T600M 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
600 0 T600M,
599 4
601 4
598 5 K598R,
602 5
597 7
603 7
596 8 E596del, E596K,
604 8
595 8 V595L, V595L,
605 8
594 9 R594Q, R594P,
606 9
593 10 N593S,
607 10 A607T,
592 11
608 11
591 11 R591H, R591C, R591L,
609 11
590 12 A590T,
610 12
589 13 G589D, G589S,
611 13 D611N, D611Y,
588 13 I588F,
612 13
587 14 T587M, T587R,
613 14
586 14 N586D,
614 14 H614del,
585 15 S585N,
615 15