KCNH2 Variant S706F

Summary of observed carriers, functional annotations, and structural context for KCNH2 S706F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

29%

90% CI: 8.0% – 49.3%

2/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

1

Publications with functional data

S706F has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 40% of WT with a standard error of 24%. 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 2 individuals with LQT2 and 8 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-5.125 0.997 -3 0.954 42

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
19695459 2009 1 0
19843919 2009 1 1
Japan Cohort 2020 1 1 0
Literature, cohort, and gnomAD – 1 1 0 –
Variant features alone – 10 8 2 –

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)
19843919 CHO None None None None

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)
19843919 CHO 62 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 S706F.
Neighbour residue Distance (Å) Observed variants
706 0 S706C, S706F,
705 5 W705fsX, W705X,
704 5 A704T, A704V,
703 6
709 6
707 6
708 6
702 7
710 8
701 9
4 9
673 10
686 10
478 10 A478D,
700 10
711 10 I711V,
762 11
669 11 G669R, G669C, G669X,
827 11
699 11 E699D, E699D,
670 12
764 12
672 12 R672C, R672H,
479 12
682 12 E682X,
713 13 M713V,
476 13 V476I,
677 13 M677T,
477 13
676 13 Q676fsX, Q676X,
763 13
481 13
6 13 G6R,
698 13 E698K, E698X,
712 14 D712N,
687 14
674 14 H674Y, H674fsX,
685 14 R685C, R685H, R685P,
668 14 S668L,
480 14 E480V,
3 14
765 14
829 14 D829A, D829E, D829E
719 14
671 14 A671G, A671Del,
697 15 L697X,
540 15 D540fsX,
720 15
761 15
683 15
760 15