KCNH2 Variant D456Y Detail

We estimate the penetrance of LQTS for KCNH2 D456Y is 87%. This variant was found in a total of 1 carriers in 2 papers or gnomAD, 1 had LQTS. D456Y is not present in gnomAD. D456Y 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 8 individuals with LQT2 and 2 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D456Y around 87% (9/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.948 0.97 -3 0.982 90
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
19038855 2009 1 0 1 Seizure
15840476 2005 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
VARIANT FEATURES ALONE: - 10 2 8 -
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)
16432067 HEK293 20 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)
16432067 HEK293 45 None None None

D456Y has 48 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
456 0 D456Y,
457 5 L457P,
455 5
453 5
459 5
460 6 D460fsX,
458 7
420 7 Y420C,
454 7
452 7
528 8 R528W, R528X, R528P,
424 8
421 9 T421fsX, T421M,
425 9
525 9 K525N, K525N,
461 9
428 10 S428L, S428fsX, S428X,
417 10
451 10 P451L,
531 10 R531W, R531Del, R531Q,
450 11
463 11 F463L, F463L, F463L,
462 11 M462Ins,
507 11 P507L, P507S,
423 11
422 12 A422T,
418 12
426 12 P426H,
504 12 A504V,
505 12 A505V,
427 12 Y427C, Y427H, Y427S,
527 13
464 13 I464X,
429 13 A429P, A429V,
419 13
449 13
508 13
526 13
529 13
416 13
506 14 I506V,
522 14 G522E,
432 14
524 14
509 14 D509N,
414 15 I414fsX,
413 15 L413P,
465 15