KCNH2 Variant L457V Detail

We estimate the penetrance of LQTS for KCNH2 L457V is 82%. We are unaware of any observations of this variant in individuals. L457V is not present in gnomAD. L457V 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L457V around 82% (8/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-2.452 0.009 1 0.715 95
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 2 8 -
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.

L457V has 32 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
457 0 L457P,
458 5
456 5 D456Y,
460 5 D460fsX,
454 6
453 6
461 6
459 6
455 7
507 9 P507S, P507L,
452 10
462 10 M462Ins,
528 11 R528W, R528X, R528P,
464 11 I464X,
463 11 F463L, F463L, F463L,
420 11 Y420C,
451 11 P451L,
450 12
505 12 A505V,
525 12 K525N, K525N,
417 12
449 12
508 13
421 13 T421M, T421fsX,
531 13 R531Del, R531W, R531Q,
509 13 D509N,
465 13
506 13 I506V,
504 13 A504V,
424 13
425 13
428 14 S428X, S428L, S428fsX,