KCNH2 Variant L15V

Summary of observed carriers, functional annotations, and structural context for KCNH2 L15V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

90% CI: 0.8% – 27.8%

1/13 effective observations

Total carriers

3

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

L15V is present in 3 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 133% of WT with a standard error of 15%. 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 (%)
-1.48 0.958 0 0.731 21

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 L15V.
Neighbour residue Distance (Å) Observed variants
15 0 L15V,
14 4
18 6 I18M,
16 6 D16A,
12 6 N12D,
13 6 T13N,
17 6
19 7 I19F,
798 7 I798fsX,
31 8 I31S,
124 8 M124T, M124R,
788 8 E788K, E788D, E788D,
825 8
795 9 V795I,
43 9 Y43D, Y43C,
42 9 I42N,
786 9
115 10 V115M,
797 10 A797T,
11 10 Q11L, Q11H, Q11H,
10 10
126 10
123 10
32 10 A32T,
20 11 R20G, R20L,
33 11 N33T
22 11 F22Y, F22S,
29 11 F29L, F29V, F29S, F29L, F29L,
21 11
787 11
826 11 T826A, T826I,
796 11 V796L, V796L, V796Del,
799 12 L799sp,
824 12
30 12 I30Del, I30T,
9 12 A9T, A9V,
125 12
800 12
785 12 G785S, G785fsX, G785D,
789 12
790 13
44 13 C44F, C44X, C44W,
794 13 V794I, V794D,
41 13 V41A,
23 13
823 13 R823W, R823fsX, R823T, R823Q,
117 13
114 13 P114S,
113 13 V113Del,
45 13 N45D, N45K, N45K,
34 14 A34T,
116 14 K116Q,
127 14
122 14
40 14
765 14
828 14
60 15 M60T,
793 15 D793N,
766 15
801 15 K801T,
35 15 R35W,
121 15 A121fsX,