KCNH2 Variant I336N

Summary of observed carriers, functional annotations, and structural context for KCNH2 I336N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

11%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I336N 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 35%. 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 (%)
-4.067 0.982 -3 0.787 12

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 I336N.
Neighbour residue Distance (Å) Observed variants
336 0
335 4 Q335X,
337 4 T337S, T337X, T337S,
334 5 P334L,
338 5
333 7
339 7
332 8
340 8 F340L, F340L, F340L,
331 8 S331N, S331T
341 8
330 9 I330V,
342 9 D342A, D342V, D342X,
329 10
343 10 L343fsX,
328 11 R328C, R328fsX, R328H,
344 11
327 11 Y327H,
345 11 G345S,
326 12 R326C, R326fsX, R326H,
346 12 D346N, D346Y, D346E, D346E,
325 13 V325M,
347 13 P347S,
324 13 L324L,
348 13
323 14 D323N, D323E, D323E,
349 14
322 14
350 14
321 15 D321Y,
351 15 S351L,