KCNH2 Variant I500Del Detail

We estimate the penetrance of LQTS for KCNH2 I500Del is 81%. This variant was found in a total of 5 carriers in 1 papers or gnomAD, 5 had LQTS. I500Del is not present in gnomAD. I500Del 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 7 individuals with LQT2 and 3 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 I500Del around 81% (12/15).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 80
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
7889573 1995 11 0 5
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)
8700910 Xeno 0 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)
8700910 Xeno 51 3.0 None None

I500Del has 37 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
500 0 I500Del,
499 4
501 5 D501N, D501Y, D501H,
530 6
503 6
502 6 M502I, M502I, M502I,
497 7 W497L, W497X,
533 7
498 7
504 8 A504V,
496 8
534 8 R534C,
527 9
531 10 R531Q, R531W, R531Del,
537 10 R537W,
505 10 A505V,
493 10 Y493H, Y493F, Y493Ins, Y493C,
532 10
529 11
506 11 I506V,
467 11
495 11 K495X,
536 12 A536X,
463 12 F463L, F463L, F463L,
494 12 F494Del,
535 13 V535M,
466 13 D466E, D466E,
528 13 R528P, R528W, R528X,
470 13 N470D,
526 13
538 13
464 14 I464X,
418 14
492 14 H492Y,
421 15 T421fsX, T421M,
471 15 F471X,
507 15 P507L, P507S,