KCNH2 Variant D323N

Summary of observed carriers, functional annotations, and structural context for KCNH2 D323N. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

5%

90% CI: 0.2% – 15.6%

0/19 effective observations

Total carriers

9

0 LQT2 · 7 unaffected

Functional studies

0

Publications with functional data

D323N is present in 9 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 118% 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 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-1.608 0.566 4 0.526 54

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 – 9 7 0 –
Variant features alone – 10 10 0 –

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 D323N.
Neighbour residue Distance (Å) Observed variants
323 0 D323N, D323E, D323E,
322 4
324 4 L324L,
321 5 D321Y,
325 5 V325M,
320 7 S320X, S320W, S320L,
326 7 R326C, R326fsX, R326H,
319 8 T319T,
327 8 Y327H,
318 8
328 8 R328C, R328fsX, R328H,
317 9 N317S,
329 9
316 10
330 10 I330V,
315 11
331 11 S331N, S331T
314 11 G314S,
332 11
313 12
333 12
312 13 R312C, R312Del, R312H,
334 13 P334L,
311 13 L311R,
335 13 Q335X,
310 14 P310X, P310L,
336 14
309 14 H309Y, H309Q, H309Q,
337 14 T337S, T337X, T337S,
308 15 M308V, M308T, M308R, M308I, M308I, M308I,
338 15