KCNH2 Variant R528A Detail

We estimate the penetrance of LQTS for KCNH2 R528A is 36%. We are unaware of any observations of this variant in individuals. R528A is not present in gnomAD. R528A has been functionally characterized in 1 papers. This residue is located in a Mild_Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R528A around 36% (3/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 39
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 7 3 -
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)
15528201 Xeno 8.7 1.3 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)
15528201 Xeno None None None

R528A has 58 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
528 0 R528X, R528P, R528W,
527 5
525 5 K525N, K525N,
531 6 R531W, R531Del, R531Q,
425 6
421 6 T421M, T421fsX,
504 6 A504V,
526 6
529 7
460 7 D460fsX,
456 8 D456Y,
530 8
459 8
505 9 A505V,
507 9 P507S, P507L,
524 9
463 9 F463L, F463L, F463L,
506 9 I506V,
420 9 Y420C,
422 9 A422T,
503 9
426 9 P426H,
428 10 S428L, S428fsX, S428X,
418 10
508 10
424 10
522 10 G522E,
457 11 L457P,
429 11 A429P, A429V,
417 11
523 11
423 11
532 11
502 12 M502I, M502I, M502I,
501 12 D501H, D501N, D501Y,
461 12
464 12 I464X,
534 12 R534C,
453 12
458 12
419 12
455 12
500 13 I500Del,
462 13 M462Ins,
533 13
452 13
563 13 W563C, W563X, W563G, W563C,
427 13 Y427S, Y427H, Y427C,
521 14
414 14 I414fsX,
430 14
454 14
509 14 D509N,
466 14 D466E, D466E,
432 15
467 15
416 15
562 15 H562Q, H562R, H562Q, H562P,