KCNH2 Variant L417M Detail

We estimate the penetrance of LQTS for KCNH2 L417M is 68%. We are unaware of any observations of this variant in individuals. L417M is not present in gnomAD. L417M 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 L417M around 68% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.903 0.994 2 0.869 81
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.

L417M has 57 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
417 0
418 5
416 5
414 5 I414fsX,
459 6
413 6 L413P,
420 6 Y420C,
415 7
419 7
421 7 T421M, T421fsX,
463 7 F463L, F463L, F463L,
462 7 M462Ins,
531 8 R531Q, R531Del, R531W,
410 9 W410X,
458 9
460 10 D460fsX,
422 10 A422T,
534 10 R534C,
456 10 D456Y,
455 10
411 10
532 10
466 10 D466E, D466E,
461 11
528 11 R528X, R528W, R528P,
424 11
423 11
535 11 V535M,
412 11 W412X,
465 12
425 12
504 12 A504V,
529 12
457 12 L457P,
464 12 I464X,
409 13 V409L, V409M, V409L,
542 13
538 13
533 13
530 13
505 13 A505V,
501 13 D501N, D501H, D501Y,
555 14
559 14 L559F, L559H,
407 14
452 14
467 14
454 14
527 14
552 14 L552S,
551 14 F551L, F551L, F551L,
408 14
453 15
469 15
426 15 P426H,
537 15 R537W,
536 15 A536X,