KCNH2 Variant S320W

Summary of observed carriers, functional annotations, and structural context for KCNH2 S320W. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

7%

90% CI: 0.5% – 26.2%

1/14 effective observations

Total carriers

4

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

S320W is present in 4 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 107% of WT with a standard error of 14%. 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 (%)
-4.72 1.0 -4 0.795 18

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 – 4 1 0 –
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 S320W.
Neighbour residue Distance (Å) Observed variants
320 0 S320X, S320W, S320L,
319 4 T319T,
321 4 D321Y,
318 5
322 5
317 7 N317S,
323 7 D323N, D323E, D323E,
316 8
324 8 L324L,
315 8
325 8 V325M,
314 9 G314S,
326 9 R326C, R326fsX, R326H,
313 10
327 10 Y327H,
312 11 R312C, R312Del, R312H,
328 11 R328C, R328fsX, R328H,
311 11 L311R,
329 11
310 12 P310X, P310L,
330 12 I330V,
309 13 H309Y, H309Q, H309Q,
331 13 S331N, S331T
308 13 M308V, M308T, M308R, M308I, M308I, M308I,
332 13
307 14 A307P,
333 14
306 14 G306W,
334 14 P334L,
305 15
335 15 Q335X,