KCNH2 Variant A429P Detail

We estimate the penetrance of LQTS for KCNH2 A429P is 41%. This variant was found in a total of 3 carriers in 1 papers or gnomAD, 2 had LQTS. A429P is not present in gnomAD. A429P has been functionally characterized in 1 papers. This residue is located in a Mild_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 A429P around 41% (5/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-4.758 0.121 -1 0.934 39
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
19668779 2009 3 1 2
LITERATURE, COHORT, AND GNOMAD: - 3 1 2 -
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.

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)
19668779 Xeno 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)
19668779 Xeno 40 -2.9 7.0 None

A429P has 43 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
429 0 A429P, A429V,
430 4
428 4 S428X, S428fsX, S428L,
426 5 P426H,
432 6
522 6 G522E,
431 7 F431L, F431L, F431L,
425 7
523 7
427 7 Y427C, Y427H, Y427S,
525 7 K525N, K525N,
526 8
566 8 C566S, C566S, C566F, C566R, C566G,
569 10 Y569C, Y569H, Y569X,
570 10
424 10
520 10
524 10
528 11 R528P, R528W, R528X,
567 11 I567T, I567M,
521 11
423 11
562 12 H562Q, H562P, H562Q, H562R,
529 12
422 12 A422T,
563 12 W563G, W563C, W563C, W563X,
574 12 M574V, M574L, M574L,
573 12
527 12
565 12
421 12 T421M, T421fsX,
611 12 Y611D,
607 13
456 13 D456Y,
452 13
420 13 Y420C,
610 14
571 14 I571V, I571L,
572 14 G572R, G572S, G572C, G572D,
564 14 L564L,
453 14
508 15
614 15 A614V, A614T,