KCNH2 Variant L532W Detail

We estimate the penetrance of LQTS for KCNH2 L532W is 68%. We are unaware of any observations of this variant in individuals. L532W is not present in gnomAD. L532W 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 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L532W around 68% (6/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 70
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 4 6 -
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 9.4 None None 0.2

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

L532W has 54 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
532 0
533 5
535 5 V535M,
418 6
529 6
530 7
534 7 R534C,
531 7 R531Q, R531Del, R531W,
536 7 A536X,
422 8 A422T,
421 8 T421fsX, T421M,
419 8
415 9
537 10 R537W,
414 10 I414fsX,
559 10 L559F, L559H,
538 10
501 10 D501Y, D501H, D501N,
417 10
563 10 W563X, W563C, W563G, W563C,
556 10
500 10 I500Del,
527 11
463 11 F463L, F463L, F463L,
504 11 A504V,
539 11
528 11 R528P, R528X, R528W,
552 11 L552S,
542 11
555 11
423 11
425 12
497 12 W497L, W497X,
416 12
420 12 Y420C,
526 12
560 12 I560fsX, I560M,
411 13
503 13
426 13 P426H,
466 13 D466E, D466E,
558 14 A558V, A558E, A558P,
459 14
562 14 H562R, H562Q, H562Q, H562P,
502 14 M502I, M502I, M502I,
553 14 L553V,
413 14 L413P,
412 14 W412X,
424 14
505 14 A505V,
551 14 F551L, F551L, F551L,
540 15 D540fsX,
460 15 D460fsX,
499 15