KCNH2 Variant C108Y

Summary of observed carriers, functional annotations, and structural context for KCNH2 C108Y. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

38%

5/14 effective observations

Total carriers

4

3 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

C108Y 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 25%. 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 (%)
-7.884 0.973 -3 0.881 62

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
28749435 2017 4 1 3
Literature, cohort, and gnomAD – 4 1 3 –
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 C108Y.
Neighbour residue Distance (Å) Observed variants
108 0 C108Y,
109 5 L109X, L109Q, L109P,
107 5 L107P,
131 5 V131L, V131L, V131fsX,
106 6 F106L, F106V, F106L, F106L,
96 6 I96V, I96T,
129 6 F129C,
98 6
110 6 V110A,
130 6 E130K,
95 6 E95K, E95G,
97 7
94 8 V94L, V94L, V94A,
51 9
28 9 K28E,
128 9 N128S,
105 10
111 10 D111V,
93 10 K93X, K93R,
69 10 L69Del, L69P,
100 11 R100G, R100Q, R100P,
127 11
99 11 Y99N, Y99S,
48 11
52 12 C52W,
74 12 T74fsX, T74M,
70 12 H70R, H70Q, H70Q,
78 12 A78T, A78P,
82 12 I82Del, I82dup, I82Ins, I82T,
112 12 V112M,
73 12 R73G, R73C, R73fsX, R73H,
66 12 C66R, C66G, C66Y,
75 13 Q75X,
104 13
79 13 A79T, A79S, A79Del, A79fsX,
47 13 G47C, G47V,
27 13 R27X, R27P,
30 13 I30Del, I30T
29 13 F29L, F29V, F29S, F29L, F29L,
71 13 G71R, G71R, G71W, G71E,
81 13 Q81E, Q81X, Q81P, Q81H, Q81H,
65 14 T65P,
50 14 E50X,
68 14 F68L, F68V, F68L, F68L,
49 15 C49R, C49G,
126 15
92 15 R92C, R92L,
103 15
64 15 C64R, C64Y,
53 15 G53S, G53R,