KCNH2 Variant S55L

Summary of observed carriers, functional annotations, and structural context for KCNH2 S55L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

52%

12/22 effective observations

Total carriers

12

10 LQT2 · 2 unaffected

Functional studies

1

Publications with functional data

S55L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 9%. 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 (%)
-3.482 0.382 -3 0.927 80

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
18508782 2008 4 2 2
Japan Cohort 2020 3 0 3
29330128 2018 4 0 4
15840476 2005 1 0 1
Literature, cohort, and gnomAD – 12 2 10 –
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)
29330128 CHO 13 9.9 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)
29330128 CHO 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 S55L.
Neighbour residue Distance (Å) Observed variants
55 0 S55L,
58 4 E58K, E58D, E58D,
57 5 A57P,
54 6 Y54N, Y54X,
56 6 R56Q,
49 6 C49R, C49G,
59 6
53 6 G53S, G53R,
857 7 E857X,
44 8 C44F, C44X, C44W,
52 8 C52W,
60 8 M60T,
859 9 T859M, T859R,
48 9
101 9 K101E,
46 10 D46Y, D46E, D46E,
858 10 I858V, I858T,
62 11 R62Q,
68 11 F68L, F68V, F68L, F68L,
50 11 E50X,
45 11 N45D, N45K, N45K,
741 11 K741R,
47 11 G47C, G47V,
803 11 D803Y, D803X,
856 12
51 12
804 12
61 12 Q61R,
41 12 V41A,
43 12 Y43D, Y43C,
855 12 S855R, S855R, S855R,
860 12
69 13 L69Del, L69P,
802 13
30 13 I30Del, I30T
100 13 R100G, R100Q, R100P,
799 13 L799sp,
854 13
66 13 C66R, C66G, C66Y,
102 14 D102H, D102V, D102X,
800 14
42 14 I42N,
861 14 N861H, N861I,
798 14 I798fsX,
740 14 C740G, C740W,
29 14 F29L, F29V, F29S, F29L, F29L,
63 14 P63H,
742 15
797 15 A797T,
28 15 K28E,