KCNH2 Variant Y542D Detail

We estimate the penetrance of LQTS for KCNH2 Y542D is 21%. We are unaware of any observations of this variant in individuals. Y542D is not present in gnomAD. Y542D has not been functionally characterized. 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 Y542D around 21% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-9.584 0.999 -3 0.957 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
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 -
VARIANT FEATURES ALONE: - 10 8 2 -
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.

Y542D 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 E544A, E544fsX,
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, V409M, V409L,
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