KCNH2 Variant L529W Detail

We estimate the penetrance of LQTS for KCNH2 L529W is 23%. We are unaware of any observations of this variant in individuals. L529W is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 5%; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. L529W 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L529W around 23% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 69
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)
16166152 Xeno 5.2 None None 0.125

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

L529W has 57 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
529 0
530 5
527 5
526 6
422 6 A422T,
532 6
421 7 T421fsX, T421M,
531 7 R531Del, R531Q, R531W,
528 7 R528X, R528P, R528W,
425 7
563 8 W563G, W563C, W563X, W563C,
426 8 P426H,
418 9
533 9
504 9 A504V,
423 10
525 10 K525N, K525N,
503 10
559 11 L559F, L559H,
419 11
500 11 I500Del,
534 11 R534C,
420 11 Y420C,
524 11
429 12 A429V, A429P,
424 12
501 12 D501N, D501H, D501Y,
463 12 F463L, F463L, F463L,
523 12
562 12 H562R, H562Q, H562Q, H562P,
535 12 V535M,
428 12 S428fsX, S428X, S428L,
417 12
505 13 A505V,
566 13 C566S, C566S, C566G, C566F, C566R,
560 13 I560M, I560fsX,
522 13 G522E,
459 13
460 13 D460fsX,
502 13 M502I, M502I, M502I,
506 13 I506V,
536 13 A536X,
456 13 D456Y,
556 14
415 14
567 14 I567T, I567M,
430 14
427 14 Y427C, Y427H, Y427S,
564 14 L564L,
414 14 I414fsX,
561 14 A561V, A561P, A561T,
558 15 A558P, A558V, A558E,
507 15 P507S, P507L,
555 15
537 15 R537W,
416 15
499 15