KCNH2 Variant K538W Detail

We estimate the penetrance of LQTS for KCNH2 K538W is 48%. We are unaware of any observations of this variant in individuals. K538W is not present in gnomAD. K538W 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 4 individuals with LQT2 and 6 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 K538W around 48% (4/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 45
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 6 4 -
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 -35.0 None None 2.0

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

K538W has 57 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
538 0
537 4 R537W,
535 5 V535M,
411 6
536 6 A536X,
542 6
541 7 R541H, R541C,
539 7
534 7 R534C,
540 7 D540fsX,
414 8 I414fsX,
533 8
407 9
415 9
497 9 W497X, W497L,
412 10 W412X,
3 10
408 10
532 10
470 10 N470D,
466 10 D466E, D466E,
410 11 W410X,
543 11 S543fsX,
402 11 H402R,
501 11 D501Y, D501H, D501N,
418 11
544 12 E544fsX, E544A,
413 12 L413P,
473 12 T473P,
409 12 V409L, V409M, V409L,
469 12
493 12 Y493F, Y493Ins, Y493H, Y493C,
463 12 F463L, F463L, F463L,
552 13 L552S,
476 13 V476I,
417 13
531 13 R531Del, R531W, R531Q,
474 13 T474I,
4 13
475 13 Y475C, Y475Del,
467 13
500 13 I500Del,
496 13
416 14
404 14
530 14
406 14
492 14 H492Y,
419 14
548 14
549 14 V549M,
498 14
403 15
545 15
462 15 M462Ins,
401 15
405 15