KCNH2 Variant D460A Detail

We estimate the penetrance of LQTS for KCNH2 D460A is 66%. We are unaware of any observations of this variant in individuals. D460A is not present in gnomAD. D460A 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 D460A around 66% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.413 0.999 -2 0.98 69
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.

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)
15975984 Xeno 22.3 7.6 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)
15975984 Xeno None None None

D460A has 50 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
460 0 D460fsX,
459 4
457 5 L457P,
461 5
456 6 D456Y,
463 6 F463L, F463L, F463L,
458 7
528 7 R528X, R528W, R528P,
464 7 I464X,
505 7 A505V,
507 7 P507S, P507L,
462 8 M462Ins,
531 8 R531Q, R531Del, R531W,
504 8 A504V,
455 9
506 9 I506V,
417 10
421 10 T421M, T421fsX,
420 10 Y420C,
465 10
453 10
454 10
525 10 K525N, K525N,
508 11
527 11
466 11 D466E, D466E,
425 11
418 12
503 12
467 12
502 12 M502I, M502I, M502I,
414 12 I414fsX,
452 12
501 13 D501Y, D501H, D501N,
424 13
534 13 R534C,
529 13
530 13
526 13
524 14
509 14 D509N,
422 14 A422T,
468 14 L468X, L468R, L468F,
413 14 L413P,
428 14 S428X, S428L, S428fsX,
416 14
410 14 W410X,
419 14
423 15
532 15