KCNH2 Variant R531Q Detail

We estimate the penetrance of LQTS for KCNH2 R531Q is 70%. This variant was found in a total of 1 carriers in 1 papers or gnomAD, 1 had LQTS. R531Q is not present in gnomAD. R531Q has been functionally characterized in 2 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 R531Q around 70% (7/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.834 1.0 1 0.953 80
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
10973849 2000 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 1 0 1 -
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)
15181157 Xeno 62.3 None None None
23546015 HEK293 68 46.0 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)
15181157 Xeno None None None
23546015 HEK293 77 11.0 None None

R531Q has 62 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
531 0 R531Q, R531Del, R531W,
504 5 A504V,
463 5 F463L, F463L, F463L,
528 6 R528X, R528W, R528P,
421 6 T421M, T421fsX,
530 6
418 6
529 7
534 7 R534C,
527 7
532 7
501 8 D501Y, D501H, D501N,
505 8 A505V,
417 8
459 8
460 8 D460fsX,
533 8
503 8
422 9 A422T,
414 9 I414fsX,
425 9
502 9 M502I, M502I, M502I,
420 9 Y420C,
500 10 I500Del,
466 10 D466E, D466E,
526 10
462 10 M462Ins,
506 10 I506V,
464 10 I464X,
419 10
456 10 D456Y,
535 11 V535M,
525 11 K525N, K525N,
415 11
467 11
507 11 P507S, P507L,
461 11
423 12
416 12
465 12
537 12 R537W,
424 12
426 12 P426H,
458 13
457 13 L457P,
498 13
413 13 L413P,
536 13 A536X,
538 13
524 13
499 13
497 13 W497X, W497L,
410 13 W410X,
411 14
563 14 W563G, W563C, W563X, W563C,
508 14
470 14 N470D,
455 14
559 14 L559F, L559H,
428 14 S428X, S428L, S428fsX,
469 15
468 15 L468X, L468R, L468F,