KCNH2 Variant G669C

Summary of observed carriers, functional annotations, and structural context for KCNH2 G669C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

8%

90% CI: 0.6% – 27.0%

1/13 effective observations

Total carriers

3

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

G669C is present in 3 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 122% of WT with a standard error of 10%. 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 (%)
-8.715 1.0 -3 0.917 6

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 – 3 1 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 G669C.
Neighbour residue Distance (Å) Observed variants
669 0 G669R, G669C, G669X,
670 4
668 4 S668L,
672 4 R672C, R672H,
671 5 A671G, A671Del,
673 7
710 7
705 7 W705fsX, W705X,
667 7 Y667X,
709 8
674 8 H674Y, H674fsX,
666 9
675 9
664 10 Q664X,
711 10 I711V,
676 10 Q676fsX, Q676X,
682 10 E682X,
708 11
706 11 S706C, S706F,
665 11 R665Q,
678 11
663 12
677 12 M677T,
679 12 R679W, R679Q,
701 12
712 12 D712N,
702 13
704 13 A704T, A704V,
675 13
665 13 R665Q,
661 13 A661V,
662 13
543 13 S543fsX,
678 14
658 14
540 14 D540fsX,
539 14
679 14 R679W, R679Q,
546 14
707 14
686 14
685 15 R685C, R685H, R685P,
713 15 M713V
661 15 A661V,