KCNH2 Variant R326H

Summary of observed carriers, functional annotations, and structural context for KCNH2 R326H. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

7%

90% CI: 0.3% – 23.9%

0/12 effective observations

Total carriers

2

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

R326H is present in 2 alleles in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 85% of WT with a standard error of 16%. 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 (%)
-2.525 0.999 -1 0.589 5

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 – 2 1 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 R326H.
Neighbour residue Distance (Å) Observed variants
326 0 R326C, R326fsX, R326H,
325 4 V325M,
327 4 Y327H,
324 5 L324L,
328 5 R328C, R328fsX, R328H,
323 7 D323N, D323E, D323E,
329 7
322 8
330 8 I330V,
321 8 D321Y,
331 8 S331N, S331T
320 9 S320X, S320W, S320L,
332 9
319 10 T319T,
333 10
318 11
334 11 P334L,
317 11 N317S,
335 11 Q335X,
316 12
336 12
315 13
337 13 T337S, T337X, T337S,
314 13 G314S,
338 13
313 14
339 14
312 14 R312C, R312Del, R312H,
340 14 F340L, F340L, F340L,
311 15 L311R,
341 15