KCNH2 Variant L416Q Detail

We estimate the penetrance of LQTS for KCNH2 L416Q is 69%. We are unaware of any observations of this variant in individuals. L416Q is not present in gnomAD. L416Q 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 L416Q around 69% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.668 0.997 -2 0.944 72
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.

L416Q has 44 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
416 0
417 5
415 5
413 5 L413P,
419 6
418 6
414 7 I414fsX,
420 8 Y420C,
412 8 W412X,
421 9 T421fsX, T421M,
551 10 F551L, F551L, F551L,
459 10
411 10
410 10 W410X,
422 11 A422T,
555 11
462 11 M462Ins,
423 11
409 11 V409L, V409L, V409M,
542 11
535 11 V535M,
552 11 L552S,
463 12 F463L, F463L, F463L,
424 12
532 12
531 12 R531W, R531Q, R531Del,
455 12
534 13 R534C,
458 13
559 13 L559H, L559F,
548 13
408 13
456 13 D456Y,
556 14
538 14
466 14 D466E, D466E,
460 14 D460fsX,
425 14
558 15 A558E, A558P, A558V,
541 15 R541C, R541H,
407 15
528 15 R528X, R528W, R528P,
529 15
461 15