KCNH2 Variant L468H Detail

We estimate the penetrance of LQTS for KCNH2 L468H is 51%. We are unaware of any observations of this variant in individuals. L468H is not present in gnomAD. L468H 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L468H around 51% (5/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.52 0.899 -3 0.938 52
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 5 5 -
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.

L468H has 37 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
468 0 L468R, L468F, L468X,
467 5
469 5
465 5
471 6 F471X,
466 7 D466E, D466E,
470 7 N470D,
464 7 I464X,
472 8 R472C, R472X,
473 9 T473P,
493 10 Y493H, Y493Ins, Y493C, Y493F,
462 10 M462Ins,
463 11 F463L, F463L, F463L,
461 11
498 11
505 11 A505V,
400 11 I400N,
410 12 W410X,
501 12 D501Y, D501N, D501H,
502 12 M502I, M502I, M502I,
490 12 A490T, A490P,
398 12 W398X, W398L,
489 12 I489I, I489F,
486 12
407 13
534 13 R534C,
494 13 F494Del,
399 13
406 13
504 13 A504V,
474 14 T474I,
460 14 D460fsX,
414 14 I414fsX,
506 15 I506V,
459 15
411 15
531 15 R531Del, R531Q, R531W,