KCNH2 Variant F129C

Summary of observed carriers, functional annotations, and structural context for KCNH2 F129C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

22%

4/12 effective observations

Total carriers

2

2 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

F129C 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 8%. 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 (%)
-5.649 0.998 -5 0.951 72

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
France Cohort 2020 2 0 2
Literature, cohort, and gnomAD – 2 0 2 –
Variant features alone – 10 8 2 –

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 F129C.
Neighbour residue Distance (Å) Observed variants
129 0 F129C,
128 4 N128S,
28 5 K28E,
110 6 V110A,
127 6
108 6 C108Y,
130 6 E130K,
109 7 L109X, L109Q, L109P,
48 7
111 7 D111V,
29 7 F29L, F29V, F29S, F29L, F29L,
30 7 I30Del, I30T,
51 8
27 8 R27X, R27P,
98 9
131 9 V131L, V131L, V131fsX,
47 9 G47C, G47V,
112 9 V112M,
126 10
106 10 F106L, F106V, F106L, F106L,
45 10 N45D, N45K, N45K,
96 10 I96V, I96T,
94 10 V94L, V94L, V94A,
52 10 C52W,
69 11 L69Del, L69P,
93 11 K93X, K93R,
107 11 L107P,
66 11 C66R, C66G, C66Y,
22 11 F22Y, F22S,
95 11 E95K, E95G,
113 11 V113Del,
49 11 C49R, C49G,
97 11
26 12 S26I,
31 12 I31S,
64 12 C64R, C64Y,
82 12 I82Del, I82dup, I82Ins, I82T,
44 12 C44F, C44X, C44W,
50 12 E50X,
100 12 R100G, R100Q, R100P,
65 12 T65P,
25 12 Q25P,
43 13 Y43D, Y43C,
125 13
59 13
46 13 D46Y, D46E, D46E,
68 13 F68L, F68V, F68L, F68L,
70 13 H70R, H70Q, H70Q,
41 13 V41A,
32 13 A32T
53 14 G53S, G53R,
91 14
54 14 Y54N, Y54X,
105 14
99 14 Y99N, Y99S,
114 14 P114S,
23 14
92 14 R92C, R92L,
19 14 I19F,
79 14 A79T, A79S, A79Del, A79fsX,
85 15 A85P, A85V,
78 15 A78T, A78P,
86 15 L86R,
18 15 I18M,