KCNH2 Variant K525C Detail

We estimate the penetrance of LQTS for KCNH2 K525C is 22%. We are unaware of any observations of this variant in individuals. K525C is not present in gnomAD. K525C has been functionally characterized in 4 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K525C around 22% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 14
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 8 2 -
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)
15181157 Xeno -19.7 None None None
15545400 Xeno -28.1 None None None
19878047 Xeno 0 None None None None
25809253 HEK293 35 -47.0 None None 1.651162791

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)
15181157 Xeno None None None
15545400 Xeno None None None
19878047 Xeno None None None
25809253 HEK293 None None None

K525C has 46 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
525 0 K525N, K525N,
522 5 G522E,
528 5 R528W, R528P, R528X,
524 5
526 6
425 7
523 7
527 7
429 7 A429V, A429P,
428 8 S428X, S428L, S428fsX,
508 8
521 9
426 9 P426H,
507 9 P507L, P507S,
456 9 D456Y,
529 10
520 10
460 10 D460fsX,
421 10 T421fsX, T421M,
506 10 I506V,
504 10 A504V,
531 11 R531Del, R531Q, R531W,
432 11
430 11
509 11 D509N,
424 11
503 12
453 12
505 12 A505V,
457 12 L457P,
530 12
510 12
422 12 A422T,
420 12 Y420C,
427 12 Y427S, Y427H, Y427C,
459 12
452 13
423 13
431 13 F431L, F431L, F431L,
463 14 F463L, F463L, F463L,
455 14
566 14 C566S, C566G, C566R, C566F, C566S,
563 15 W563C, W563G, W563X, W563C,
454 15
418 15
502 15 M502I, M502I, M502I,