KCNH2 Variant V459A Detail

We estimate the penetrance of LQTS for KCNH2 V459A is 69%. We are unaware of any observations of this variant in individuals. V459A is not present in gnomAD. V459A has not been functionally characterized. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V459A around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.707 0.541 0 0.921 77
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 LQT2 Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 4 6 -
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.

V459A has 53 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 since the functional KV11.1 channel (protein product of KCNH2/hERG) 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
459 0
460 4 D460fsX,
458 5
456 5 D456Y,
462 6 M462Ins,
417 6
463 6 F463L, F463L, F463L,
461 6
457 6 L457P,
420 7 Y420C,
455 7
421 8 T421fsX, T421M,
531 8 R531W, R531Q, R531Del,
528 8 R528X, R528W, R528P,
418 9
464 9 I464X,
454 10
414 10 I414fsX,
465 10
453 10
413 10 L413P,
416 10
504 10 A504V,
505 10 A505V,
424 11
466 11 D466E, D466E,
419 11
425 11
452 11
507 11 P507S, P507L,
410 12 W410X,
422 12 A422T,
534 12 R534C,
415 12
525 12 K525N, K525N,
423 13
527 13
529 13
506 13 I506V,
467 13
532 14
501 14 D501N, D501Y, D501H,
451 14 P451L,
530 14
428 14 S428X, S428fsX, S428L,
503 14
502 15 M502I, M502I, M502I,
411 15
426 15 P426H,
468 15 L468F, L468X, L468R,
526 15
508 15
469 15