KCNH2 Variant L349F

Summary of observed carriers, functional annotations, and structural context for KCNH2 L349F. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

8%

90% CI: 0.3% – 25.2%

0/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L349F 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: 181% of WT with a standard error of 33%. 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 (%)
-1.318 0.982 -1 0.545 1

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 L349F.
Neighbour residue Distance (Å) Observed variants
349 0
348 4
350 4
347 5 P347S,
351 5 S351L,
346 7 D346N, D346Y, D346E, D346E,
352 7
345 8 G345S,
353 8 T353S, T353S,
344 8
354 8
343 9 L343fsX,
355 9 D355G,
342 10 D342A, D342V, D342X,
356 10 R356C, R356H,
341 11
357 11 E357D, E357D,
340 11 F340L, F340L, F340L,
358 11
339 12
359 12 I359V,
338 13
360 13
337 13 T337S, T337X, T337S,
361 13
336 14
362 14
335 14 Q335X,
363 14 I363X,
334 15 P334L,
364 15 K364X