KCNH2 Variant L552S

Summary of observed carriers, functional annotations, and structural context for KCNH2 L552S. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

30%

90% CI: 30.5% – 45.9%

40/133 effective observations

Total carriers

123

39 LQT2 · 58 unaffected

Functional studies

1

Publications with functional data

L552S is present in 46 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

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.

Variant features alone are equivalent to phenotyping 1 individuals with LQT2 and 9 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.751 1.0 -2 0.948 29

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source 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 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Functional data

Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.

Homomeric channel data

Published electrophysiology measurements (homomeric).
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

Heteromeric channel data

Published electrophysiology measurements (heteromeric).
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

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that 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 15Å window.

Previously observed variants near L552S.
Neighbour residue Distance (Å) Observed variants
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 L559F, L559H,
546 10
558 11 A558P, A558E, A558V,
557 11
659 11
536 11 A536X,
532 11
418 11
416 11
658 11
662 12
545 12
560 12 I560fsX, I560M,
540 12 D540fsX,
656 12 F656L, F656L, F656L,
538 13
544 13 E544A, E544fsX,
422 13 A422T,
651 13 M651K,
541 13 R541C, R541H,
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 W563G, W563C, W563C, W563X,
423 14
413 15 L413P,
663 15
661 15 A661V,
674 15 H674Y, H674fsX
561 15 A561T, A561P, A561V,
421 15 T421fsX, T421M,
660 15 S660L,