KCNH2 Variant S668L

Summary of observed carriers, functional annotations, and structural context for KCNH2 S668L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

1/12 effective observations

Total carriers

2

0 LQT2 · 2 unaffected

Functional studies

0

Publications with functional data

S668L is present in 2 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 87% 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.

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 (%)
-5.815 0.999 -3 0.919 7

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
Literature, cohort, and gnomAD – 2 2 0 –
Variant features alone – 10 9 1 –

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

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 S668L.
Neighbour residue Distance (Å) Observed variants
668 0 S668L,
669 4 G669R, G669C, G669X
672 5 R672C, R672H,
671 5 A671G, A671Del,
670 6
664 7 Q664X,
667 7 Y667X,
666 7
665 7 R665Q,
710 9
663 9
678 9
709 10
661 10 A661V,
675 10
673 10
682 10 E682X,
662 10
705 10 W705X, W705fsX,
674 10 H674fsX, H674Y,
679 11 R679Q, R679W,
675 11
711 11 I711V,
676 12 Q676fsX, Q676X,
546 12
660 12 S660L,
658 13
708 13
712 13 D712N,
674 13 H674fsX, H674Y,
676 13 Q676fsX, Q676X,
665 14 R665Q,
661 14 A661V,
547 14 A547T,
706 14 S706C, S706F,
681 14 R681W,
659 14
671 14 A671G, A671Del,
677 14 M677T,
677 15 M677T,
657 15 G657V, G657S,
654 15
680 15
685 15 R685H, R685P, R685C,