KCNH2 Variant Y545F Detail

We estimate the penetrance of LQTS for KCNH2 Y545F is 13%. We are unaware of any observations of this variant in individuals. Y545F is not present in gnomAD. We have tested the trafficking efficiency of this variant, 135% of WT with a standard error of %; in our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong. Y545F has not been functionally characterized. 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 Y545F around 13% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-3.6 0.73 3 0.817 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 9 1 -
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.

Y545F has 38 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
545 0
544 5 E544A, E544fsX,
546 6
548 6
547 7 A547T,
543 7 S543fsX,
549 9 V549M,
412 9 W412X,
681 9 R681W,
542 9
541 9 R541H, R541C,
540 11 D540fsX,
678 11
666 11
408 11
550 11
3 11
551 12 F551L, F551L, F551L,
685 12 R685C, R685P, R685H,
674 12 H674Y, H674fsX,
665 12 R665Q,
552 12 L552S,
677 12 M677T,
409 12 V409L, V409L, V409M,
539 12
662 12
411 13
682 13 E682X,
415 14
405 14
553 14 L553V,
673 15
680 15
538 15
675 15
667 15 Y667X,
684 15
698 15 E698K, E698X,