KCNH2 Variant L530C Detail

We estimate the penetrance of LQTS for KCNH2 L530C is 77%. We are unaware of any observations of this variant in individuals. L530C is not present in gnomAD. L530C 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 L530C around 77% (7/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 71
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)
19878047 Xeno 21.8 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)
19878047 Xeno None None None

L530C has 49 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
530 0
529 5
527 5
500 6 I500Del,
531 6 R531Q, R531W, R531Del,
533 6
504 6 A504V,
503 7
532 7
501 7 D501N, D501Y, D501H,
534 8 R534C,
528 8 R528P, R528W, R528X,
526 8
502 9 M502I, M502I, M502I,
421 10 T421fsX, T421M,
499 10
505 10 A505V,
418 10
463 10 F463L, F463L, F463L,
422 11 A422T,
497 11 W497L, W497X,
506 11 I506V,
535 11 V535M,
425 11
536 11 A536X,
537 11 R537W,
498 12
525 12 K525N, K525N,
524 12
563 13 W563X, W563C, W563C, W563G,
460 13 D460fsX,
426 13 P426H,
496 13
417 13
466 13 D466E, D466E,
419 13
467 13
414 13 I414fsX,
507 14 P507L, P507S,
538 14
459 14
523 14
420 14 Y420C,
464 14 I464X,
415 14
423 14
508 15
559 15 L559H, L559F,
493 15 Y493H, Y493F, Y493Ins, Y493C,