KCNH2 Variant R534L Detail

We estimate the penetrance of LQTS for KCNH2 R534L is 24%. We are unaware of any observations of this variant in individuals. R534L is not present in gnomAD. We have tested the trafficking efficiency of this variant, 0% of WT with a standard error of 0%; 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. R534L 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 R534L around 24% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.709 1.0 -2 0.976 81
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)
23546015 HEK293 11 -14.0 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)
23546015 HEK293 37 -4.0 None None

R534L has 59 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
534 0 R534C,
501 5 D501H, D501Y, D501N,
533 5
537 6 R537W,
535 7 V535M,
538 7
531 7 R531W, R531Del, R531Q,
466 7 D466E, D466E,
463 7 F463L, F463L, F463L,
414 7 I414fsX,
532 7
418 8
536 8 A536X,
530 8
497 8 W497L, W497X,
500 8 I500Del,
504 9 A504V,
470 9 N470D,
411 9
467 9
415 9
417 10
502 10 M502I, M502I, M502I,
498 10
410 10 W410X,
493 11 Y493C, Y493Ins, Y493H, Y493F,
505 11 A505V,
421 11 T421fsX, T421M,
503 11
542 11
462 11 M462Ins,
529 11
469 11
464 11 I464X,
465 11
539 12
407 12
413 12 L413P,
496 12
499 12
459 12
527 12
528 12 R528P, R528W, R528X,
419 12
541 13 R541C, R541H,
416 13
460 13 D460fsX,
412 13 W412X,
468 13 L468F, L468X, L468R,
422 13 A422T,
471 13 F471X,
473 13 T473P,
540 14 D540fsX,
408 14
461 14
506 14 I506V,
420 14 Y420C,
492 15 H492Y,
409 15 V409L, V409M, V409L,