KCNH2 Variant L539P Detail

We estimate the penetrance of LQTS for KCNH2 L539P is 27%. We are unaware of any observations of this variant in individuals. L539P is not present in gnomAD. L539P 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 L539P around 27% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-6.642 1.0 -3 0.973 28
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.

L539P has 46 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
539 0
540 4 D540fsX,
536 5 A536X,
542 5
543 6 S543fsX,
535 6 V535M,
538 7
541 8 R541H, R541C,
537 9 R537W,
552 9 L552S,
549 9 V549M,
544 10 E544fsX, E544A,
3 10
533 10
415 11
411 11
548 11
674 11 H674fsX, H674Y,
670 11
412 11 W412X,
532 11
553 11 L553V,
534 12 R534C,
673 12
667 12 Y667X,
545 12
546 13
497 13 W497X, W497L,
414 13 I414fsX,
556 13
4 13
551 13 F551L, F551L, F551L,
408 13
418 13
671 14 A671G, A671Del,
555 14
547 14 A547T,
550 14
658 14
669 14 G669R, G669X, G669C,
407 14
677 15 M677T,
419 15
402 15 H402R,
662 15
702 15