KCNH2 Variant R366L

Summary of observed carriers, functional annotations, and structural context for KCNH2 R366L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

90% CI: 1.0% – 31.3%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

R366L has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 83% of WT with a standard error of 10%. 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 (%)
-5.603 0.979 -2 0.814 13

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 – 0 0 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 R366L.
Neighbour residue Distance (Å) Observed variants
366 0 R366X, R366Q,
365 4 E365G,
367 4 T367S, T367S,
364 5 K364X,
368 5 H368Y,
363 7 I363X,
369 7 N369K, N369K,
362 8
370 8
361 8
371 8
360 9
372 9
359 10 I359V,
373 10
358 11
374 11
357 11 E357D, E357D,
375 11
356 12 R356C, R356H,
376 12 Q376sp, Q376R,
355 13 D355G,
377 13
354 13
378 13
353 14 T353S, T353S,
379 14 S379Y,
352 14
380 14 L380X
351 15 S351L,
381 15