KCNH2 Variant S428L Detail

We estimate the penetrance of LQTS for KCNH2 S428L is 26%. This variant was found in a total of 12 carriers in 4 papers or gnomAD, 2 had LQTS. S428L is present in 5 alleles in gnomAD. S428L 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 3 individuals with LQT2 and 7 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 S428L around 26% (5/22).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.068 0.391 -3 0.922 38
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
28438721 2017 4 4
Japan Cohort 2020 1 1 0
11854117 2002 1 0 1
24606995 2014 1 0 1
LITERATURE, COHORT, AND GNOMAD: - 12 10 2 -
VARIANT FEATURES ALONE: - 10 7 3 -
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.

S428L has 48 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
428 0 S428X, S428fsX, S428L,
429 4 A429V, A429P,
427 5 Y427C, Y427H, Y427S,
425 6
432 6
426 6 P426H,
430 6
431 7 F431L, F431L, F431L,
424 7
525 8 K525N, K525N,
522 9 G522E,
452 9
423 9
566 10 C566F, C566R, C566G, C566S, C566S,
456 10 D456Y,
528 10 R528P, R528W, R528X,
526 10
420 10 Y420C,
523 10
421 10 T421M, T421fsX,
422 11 A422T,
453 11
562 11 H562R, H562P, H562Q, H562Q,
611 11 Y611D,
569 12 Y569H, Y569X, Y569C,
607 12
520 12
529 12
524 12
563 12 W563C, W563C, W563X, W563G,
450 13
527 13
565 13
570 13
455 13
521 13
567 13 I567M, I567T,
451 14 P451L,
610 14
460 14 D460fsX,
459 14
457 14 L457P,
454 14
573 14
531 14 R531Del, R531Q, R531W,
608 14
559 15 L559H, L559F,
419 15