KCNH2 Variant R537W Detail

We estimate the penetrance of LQTS for KCNH2 R537W is 57%. This variant was found in a total of 2 carriers in 1 papers or gnomAD, 1 had LQTS. R537W is not present in gnomAD. R537W 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 5 individuals with LQT2 and 5 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 R537W around 57% (6/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-7.668 1.0 -3 0.795 59
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
19184172 2 1 1
LITERATURE, COHORT, AND GNOMAD: - 2 1 1 -
VARIANT FEATURES ALONE: - 10 5 5 -
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 13.9 None None 1.0

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

R537W has 52 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
537 0 R537W,
538 4
497 5 W497L, W497X,
536 5 A536X,
534 6 R534C,
533 6
535 7 V535M,
501 8 D501H, D501Y, D501N,
539 9
496 9
470 9 N470D,
493 10 Y493Ins, Y493C, Y493H, Y493F,
500 10 I500Del,
532 10
540 10 D540fsX,
411 10
542 10
466 11 D466E, D466E,
541 11 R541H, R541C,
414 11 I414fsX,
498 11
492 11 H492Y,
530 11
407 12
467 12
475 12 Y475C, Y475Del,
415 12
531 12 R531Del, R531Q, R531W,
499 12
418 12
3 13
473 13 T473P,
476 13 V476I,
463 13 F463L, F463L, F463L,
402 13 H402R,
469 13
502 13 M502I, M502I, M502I,
410 13 W410X,
474 13 T474I,
504 13 A504V,
543 14 S543fsX,
471 14 F471X,
408 14
412 14 W412X,
4 14
495 14 K495X,
494 14 F494Del,
489 14 I489I, I489F,
503 14
417 15
529 15
477 15