KCNH2 Variant L413P Detail

We estimate the penetrance of LQTS for KCNH2 L413P is 78%. This variant was found in a total of 2 carriers in 2 papers or gnomAD, 2 had LQTS. L413P is not present in gnomAD. L413P has been functionally characterized in 1 papers. 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L413P around 78% (9/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.925 0.994 -3 0.951 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
12442276 2002 2 0 2
26496715 2015 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 2 0 2 -
VARIANT FEATURES ALONE: - 10 3 7 -
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
18218237 HEK293 None None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
18218237 HEK293 100 None None None

L413P has 42 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
413 0 L413P,
414 5 I414fsX,
410 5 W410X,
416 5
417 6
409 7 V409M, V409L, V409L,
415 7
411 7
412 7 W412X,
462 8 M462Ins,
418 9
408 9
407 10
459 10
463 10 F463L, F463L, F463L,
419 10
406 10
466 10 D466E, D466E,
542 11
420 12 Y420C,
465 12
534 12 R534C,
458 12
538 12
535 12 V535M,
541 12 R541H, R541C,
421 13 T421M, T421fsX,
461 13
531 13 R531Del, R531W, R531Q,
469 13
405 13
455 14
551 14 F551L, F551L, F551L,
460 14 D460fsX,
532 14
404 14
464 14 I464X,
552 15 L552S,
470 15 N470D,
422 15 A422T,
456 15 D456Y,
548 15