KCNH2 Variant L523M Detail

We estimate the penetrance of LQTS for KCNH2 L523M is 9%. This variant was found in a total of 1 carriers in 0 papers or gnomAD (version 4), 0 had LQTS. L523M is present in 1 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 105% of WT with a standard error of 13%; 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. L523M 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 0 individuals with LQT2 and 10 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L523M around 9% (0/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-1.917 1.0 2 0.639 16
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: - 1 0 0 -
VARIANT FEATURES ALONE: - 10 10 0 -
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.

L523M has 34 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
523 0
522 4 G522E,
524 5
526 6
521 6
525 7 K525N, K525N,
429 7 A429P, A429V,
520 8
527 9
430 9
425 10
428 10 S428X, S428L, S428fsX,
426 10 P426H,
528 11 R528W, R528X, R528P,
508 11
432 11
529 12
574 12 M574V, M574L, M574L,
570 13
510 13
431 13 F431L, F431L, F431L,
566 13 C566F, C566S, C566G, C566R, C566S,
567 13 I567M, I567T,
530 14
503 14
506 14 I506V,
507 14 P507S, P507L,
427 14 Y427C, Y427S, Y427H,
509 15 D509N,
573 15
504 15 A504V,
563 15 W563C, W563G, W563X, W563C,
569 15 Y569C, Y569X, Y569H,
421 15 T421fsX, T421M,