KCNH2 Variant L338R

Summary of observed carriers, functional annotations, and structural context for KCNH2 L338R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

9%

90% CI: 0.4% – 27.0%

0/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L338R has not been reported in gnomAD. This residue resides in a Non_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 125% of WT with a standard error of 7%. 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 (%)
-3.887 0.551 -2 0.822 4

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 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 L338R.
Neighbour residue Distance (Å) Observed variants
338 0
337 4 T337S, T337X, T337S,
339 4
336 5
340 5 F340L, F340L, F340L,
335 7 Q335X,
341 7
334 8 P334L,
342 8 D342A, D342V, D342X,
333 8
343 8 L343fsX,
332 9
344 9
331 10 S331N, S331T
345 10 G345S,
330 11 I330V,
346 11 D346N, D346Y, D346E, D346E,
329 11
347 11 P347S,
328 12 R328C, R328fsX, R328H,
348 12
327 13 Y327H,
349 13
326 13 R326C, R326fsX, R326H,
350 13
325 14 V325M,
351 14 S351L,
324 14 L324L,
352 14
323 15 D323N, D323E, D323E,
353 15 T353S, T353S,