KCNQ1 Variant D462G Detail

We estimate the penetrance of LQTS for KCNQ1 D462G is 10%. We are unaware of any observations of this variant in individuals. D462G is not present in gnomAD. D462G 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 D462G around 10% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.24 0.004 0 0.579 2
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.

D462G 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
462 0
461 4
463 4 S463T,
460 5 G460S, G460D, G460C,
464 5 S464P,
459 7 D459N, D459V,
465 7
458 8
466 8
457 8
467 8 K467R,
456 9 F456L, F456L, F456L,
468 9 S468G, S468N,
455 10 H455Y, H455Q, H455Q, H455R,
469 10
454 11
470 11
453 11
471 11
452 12 R452Q, R452W, R452L,
472 12 L472P,
451 13 R451Q, R451W,
473 13 E473Q,
450 13 E450K,
474 13
449 14 E449K,
475 14
448 14 P448R, P448Q, P448L, P448S,
476 14 M476L, M476L, M476V,
447 15 P447H,
477 15 P477L, P477T,