KCNQ1 Variant A486V Detail

We estimate the penetrance of LQTS for KCNQ1 A486V is 13%. We are unaware of any observations of this variant in individuals. A486V is not present in gnomAD. A486V has not been functionally characterized. This residue is located in a Non_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 A486V around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.05 0.1 0 0.617 1
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
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.

A486V 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
486 0 A486T,
485 4 F485S,
487 4 E487K,
484 5
488 5 D488E, D488E,
483 7
489 7
482 8 T482N, T482A, T482S, T482S,
490 8
481 8
491 8
480 9 M480T,
492 9 L492ins,
479 10 F479L, F479L, F479L,
493 10 G493A,
478 11 H478Y,
494 11
477 11 P477L, P477T,
495 11 T495S, T495S, T495A,
476 12 M476L, M476L, M476V,
496 12
475 13
497 13 L497P,
474 13
498 13
473 14 E473Q,
499 14 P499S,
472 14 L472P,
500 14 I500L, I500V,
471 15
501 15 T501A,