KCNH2 Variant L415M Detail

We estimate the penetrance of LQTS for KCNH2 L415M is 35%. We are unaware of any observations of this variant in individuals. L415M is not present in gnomAD. L415M 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L415M around 35% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.903 0.989 2 0.846 49
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 7 3 -
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.

L415M has 52 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
415 0
416 5
414 5 I414fsX,
418 5
412 6 W412X,
419 6
535 7 V535M,
542 7
417 7
413 7 L413P,
411 7
552 8 L552S,
532 9
538 9
551 9 F551L, F551L, F551L,
534 9 R534C,
555 9
410 10 W410X,
421 10 T421M, T421fsX,
539 11
409 11 V409L, V409L, V409M,
536 11 A536X,
548 11
422 11 A422T,
541 11 R541H, R541C,
420 11 Y420C,
531 11 R531Q, R531W, R531Del,
463 11 F463L, F463L, F463L,
408 11
533 11
556 11
559 12 L559H, L559F,
537 12 R537W,
549 12 V549M,
462 12 M462Ins,
459 12
543 12 S543fsX,
407 12
466 12 D466E, D466E,
423 12
540 13 D540fsX,
553 13 L553V,
529 14
545 14
544 14 E544fsX, E544A,
550 14
547 14 A547T,
558 14 A558V, A558P, A558E,
530 14
424 14
554 14
501 15 D501H, D501N, D501Y,