KCNQ1 Variant D454V Detail

We estimate the penetrance of LQTS for KCNQ1 D454V is 15%. We are unaware of any observations of this variant in individuals. D454V is not present in gnomAD. D454V 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 1 individuals with LQT1 and 9 unaffected individuals. These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D454V around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.26 0.008 -3 0.575 14
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 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.

D454V 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
454 0
453 4
455 4 H455Y, H455Q, H455Q, H455R,
452 5 R452Q, R452W, R452L,
456 5 F456L, F456L, F456L,
451 7 R451Q, R451W,
457 7
450 8 E450K,
458 8
449 8 E449K,
459 8 D459N, D459V,
448 9 P448R, P448Q, P448L, P448S,
460 9 G460S, G460D, G460C,
447 10 P447H,
461 10
446 11 D446E, D446E, D446E, D446E, D446N,
462 11
445 11
463 11 S463T,
444 12 T444M, T444K,
464 12 S464P,
443 13
465 13
442 13 H442R,
466 13
441 14 P441S,
467 14 K467R,
440 14
468 14 S468G, S468N,
439 15
469 15