KCNH2 Variant D466E Detail

We estimate the penetrance of LQTS for KCNH2 D466E is 51%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 1 had LQTS. D466E is not present in gnomAD. D466E 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D466E around 51% (6/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.707 0.999 1 0.905 62
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
Japan Cohort 2020 2 1 1
LITERATURE, COHORT, AND GNOMAD: - 2 1 1 -
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.

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)
23980197 Xeno 0.2 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)
23980197 Xeno None None None

D466E has 62 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
466 0 D466E, D466E,
467 5
465 5
469 5
470 5 N470D,
463 6 F463L, F463L, F463L,
468 7 L468X, L468R, L468F,
534 7 R534C,
462 7 M462Ins,
464 7 I464X,
410 7 W410X,
414 8 I414fsX,
501 8 D501H, D501Y, D501N,
407 9
411 9
471 9 F471X,
473 10 T473P,
531 10 R531Del, R531Q, R531W,
493 10 Y493Ins, Y493C, Y493H, Y493F,
461 10
505 10 A505V,
538 10
504 10 A504V,
417 10
498 10
413 10 L413P,
537 11 R537W,
502 11 M502I, M502I, M502I,
459 11
460 11 D460fsX,
406 11
418 12
472 12 R472C, R472X,
533 12
400 12 I400N,
535 12 V535M,
415 12
497 13 W497L, W497X,
500 13 I500Del,
408 13
409 13 V409L, V409L, V409M,
503 13
474 13 T474I,
532 13
530 13
458 13
416 14
506 14 I506V,
489 14 I489I, I489F,
541 14 R541H, R541C,
402 14 H402R,
421 14 T421M, T421fsX,
412 14 W412X,
536 14 A536X,
528 14 R528X, R528W, R528P,
499 14
542 14
496 14
490 15 A490T, A490P,
494 15 F494Del,
404 15
401 15