KCNH2 Variant Y542A Detail

We estimate the penetrance of LQTS for KCNH2 Y542A is 21%. We are unaware of any observations of this variant in individuals. Y542A is not present in gnomAD. Y542A has been functionally characterized in 2 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 2 individuals with LQT2 and 8 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y542A around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
None None None None 20
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
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 14.8 28.8 None None
27317659 HEK293 16.7 None None 0.103773585

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
27317659 HEK293 None None None

Y542A has 44 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
542 0
541 5 R541H, R541C,
412 5 W412X,
539 5
540 6 D540fsX,
535 6 V535M,
538 6
543 6 S543fsX,
411 7
415 7
552 8 L552S,
544 8 E544fsX, E544A,
548 8
536 8 A536X,
549 9 V549M,
408 9
414 9 I414fsX,
545 9
3 10
551 10 F551L, F551L, F551L,
537 10 R537W,
409 10 V409L, V409L, V409M,
413 11 L413P,
407 11
534 11 R534C,
418 11
416 11
546 11
532 11
547 11 A547T,
410 12 W410X,
553 12 L553V,
555 12
533 12
419 12
550 13
417 13
556 13
674 13 H674fsX, H674Y,
402 14 H402R,
405 14
466 14 D466E, D466E,
404 14
4 15