KCNH2 Variant V455L Detail

We estimate the penetrance of LQTS for KCNH2 V455L is 73%. We are unaware of any observations of this variant in individuals. V455L is not present in gnomAD. V455L 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 V455L around 73% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.528 0.193 1 0.725 84
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 3 7 -
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.

V455L has 33 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
455 0
454 4
456 5 D456Y,
458 5
453 6
452 6
457 7 L457P,
459 7
451 7 P451L,
420 7 Y420C,
460 9 D460fsX,
424 9
450 10
417 10
461 10
462 11 M462Ins,
449 11
421 11 T421M, T421fsX,
416 12
528 12 R528W, R528P, R528X,
425 13
463 13 F463L, F463L, F463L,
423 13
428 13 S428fsX, S428X, S428L,
418 13
419 14
413 14 L413P,
531 14 R531Q, R531W, R531Del,
525 14 K525N, K525N,
427 14 Y427C, Y427S, Y427H,
422 14 A422T,
414 15 I414fsX,
464 15 I464X,