KCNH2 Variant T526W Detail

We estimate the penetrance of LQTS for KCNH2 T526W is 41%. We are unaware of any observations of this variant in individuals. T526W is not present in gnomAD. T526W 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 T526W around 41% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 37
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
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)
16166152 Xeno -39.5 None None 4.0

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)
16166152 Xeno None None None

T526W has 47 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
526 0
527 4
529 6
525 6 K525N, K525N,
523 6
524 6
528 6 R528P, R528W, R528X,
425 7
522 8 G522E,
426 8 P426H,
429 8 A429P, A429V,
530 8
421 10 T421fsX, T421M,
531 10 R531Q, R531W, R531Del,
428 10 S428fsX, S428L, S428X,
504 10 A504V,
503 10
422 10 A422T,
430 11
563 11 W563C, W563C, W563G, W563X,
521 11
508 11
506 12 I506V,
532 12
566 12 C566G, C566R, C566S, C566S, C566F,
423 12
507 13 P507S, P507L,
424 13
505 13 A505V,
567 13 I567T, I567M,
500 13 I500Del,
520 13
456 13 D456Y,
427 13 Y427S, Y427C, Y427H,
460 13 D460fsX,
420 13 Y420C,
432 13
418 14
533 14
502 14 M502I, M502I, M502I,
562 14 H562Q, H562R, H562P, H562Q,
431 14 F431L, F431L, F431L,
501 14 D501Y, D501N, D501H,
463 14 F463L, F463L, F463L,
570 14
559 15 L559F, L559H,
459 15