KCNH2 Variant L552S Detail

We estimate the penetrance of LQTS for KCNH2 L552S is 30%. This variant was found in a total of 123 carriers in 9 papers or gnomAD (version 4), 39 had LQTS. L552S is present in 46 alleles in gnomAD. We have tested the trafficking efficiency of this variant, 53% of WT with a standard error of 11%; 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. L552S has been functionally characterized in 1 papers. 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 1 individuals with LQT2 and 9 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 L552S around 30% (40/133).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-5.751 1.0 -2 0.948 29
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
16754261 2006 77 13
29622001 2018 73 0 22
26063740 2 0 2
11854117 2002 4 0 4
23098067 2012 1 0 1
10841244 2000 42 25 12
10973849 2000 1 0 1
15840476 2005 1 0 1
19160088 2 2
LITERATURE, COHORT, AND GNOMAD: - 123 58 39 -
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.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
10841244 COS7 60 -8.4 None None 0.192616372

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
10841244 COS7 None None None

L552S has 56 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
552 0 L552S,
551 5 F551L, F551L, F551L,
553 5 L553V,
555 5
549 6 V549M,
556 6
548 6
550 7
554 8
542 8
415 8
535 9 V535M,
543 9 S543fsX,
539 9
547 9 A547T,
419 10
412 10 W412X,
655 10
559 10 L559H, L559F,
546 10
558 11 A558P, A558V, A558E,
557 11
659 11
536 11 A536X,
532 11
418 11
416 11
658 11
662 12
545 12
560 12 I560M, I560fsX,
540 12 D540fsX,
656 12 F656L, F656L, F656L,
538 13
544 13 E544fsX, E544A,
422 13 A422T,
651 13 M651K,
541 13 R541H, R541C,
414 13 I414fsX,
411 13
654 14
533 14
657 14 G657S, G657V,
650 14 L650X,
417 14
646 14
665 14 R665Q,
563 14 W563C, W563C, W563X, W563G,
423 14
413 15 L413P,
663 15
661 15 A661V,
674 15 H674fsX, H674Y,
561 15 A561V, A561P, A561T,
421 15 T421M, T421fsX,
660 15 S660L,