KCNH2 Variant P334L

Summary of observed carriers, functional annotations, and structural context for KCNH2 P334L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

13%

5/15 effective observations

Total carriers

5

4 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

P334L has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 0%. 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 (%)
-6.767 0.974 -3 0.82 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
Japan Cohort 2020 2 0 2
France Cohort 2020 3 1 2
Literature, cohort, and gnomAD – 5 1 4 –
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 P334L.
Neighbour residue Distance (Å) Observed variants
334 0 P334L,
333 4
335 4 Q335X,
332 5
336 5
331 7 S331N, S331T
337 7 T337S, T337X, T337S,
330 8 I330V,
338 8
329 8
339 8
328 9 R328C, R328fsX, R328H,
340 9 F340L, F340L, F340L,
327 10 Y327H,
341 10
326 11 R326C, R326fsX, R326H,
342 11 D342A, D342V, D342X,
325 11 V325M,
343 11 L343fsX,
324 12 L324L,
344 12
323 13 D323N, D323E, D323E,
345 13 G345S,
322 13
346 13 D346N, D346Y, D346E, D346E,
321 14 D321Y,
347 14 P347S,
320 14 S320X, S320W, S320L,
348 14
319 15 T319T,
349 15