KCNH2 Variant R328C
Summary of observed carriers, functional annotations, and structural context for KCNH2 R328C. Data combine curated literature, international cohorts, and gnomAD observations.
Estimated LQT2 penetrance
2%
90% CI: 2.6% – 7.8%
8/457 effective observations
Total carriers
447
8 LQT2 · 163 unaffected
Functional studies
2
Publications with functional data
We have tested the trafficking efficiency of this variant: 83% of WT with a standard error of 8%. 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
| PROVEAN | PolyPhen-2 | BLAST-PSSM | REVEL | Penetrance Density LQT2 (%) |
|---|---|---|---|---|
| -4.057 | 1.0 | -4 | 0.77 | 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
| Source | Year | Carriers | Unaffected | LQT2 | Other Disease |
|---|---|---|---|---|---|
| Japan Cohort | 2020 | 1 | 0 | 1 | |
| France Cohort | 2020 | 1 | 1 | 0 | |
| 23098067 | 2012 | 1 | 0 | 1 | |
| 16253915 | 2005 | 2 | 1 | 1 | |
| 15840476 | 2005 | 2 | 0 | 2 | |
| 16922724 | 2006 | 3 | 0 | 3 | |
| 24217263 | 2013 | 1 | 0 | congenital LQT | |
| 29650123 | 2018 | 1 | 0 | ||
| Literature, cohort, and gnomAD | – | 447 | 163 | 8 | – |
| Variant features alone | – | 10 | 10 | 0 | – |
Totals may differ from individual publications due to duplicate patients removed during curation.
Functional data
Functional assay results from published electrophysiology studies. Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V1/2 activation and inactivation are the voltages at which half of the maximal current is reached, in mV. Recovery from inactivation and deactivation time are ratios of characteristic time constants with wildtype. HM indicates homomeric channels, HT indicates heteromeric channels.
Homomeric channel data
| PubMed ID | Cell Type | S.S Peak (%WT) | Peak Tail IKr (%WT) | V1/2 Act. | V1/2 Inact. | Recov. Inact. | Deactivation (%WT) |
|---|---|---|---|---|---|---|---|
| 16253915 | Xeno | 150 | None | None | None | None | |
| 16432067 | HEK293 | 85 | None | None | None | None |
Heteromeric channel data
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.
| Neighbour residue | Distance (Å) | Observed variants |
|---|---|---|
| 328 | 0 | R328C, R328fsX, R328H, |
| 327 | 4 | Y327H, |
| 329 | 4 | |
| 326 | 5 | R326C, R326fsX, R326H, |
| 330 | 5 | I330V, |
| 325 | 7 | V325M, |
| 331 | 7 | S331N, S331T |
| 324 | 8 | L324L, |
| 332 | 8 | |
| 323 | 8 | D323N, D323E, D323E, |
| 333 | 8 | |
| 322 | 9 | |
| 334 | 9 | P334L, |
| 321 | 10 | D321Y, |
| 335 | 10 | Q335X, |
| 320 | 11 | S320X, S320W, S320L, |
| 336 | 11 | |
| 319 | 11 | T319T, |
| 337 | 11 | T337S, T337X, T337S, |
| 318 | 12 | |
| 338 | 12 | |
| 317 | 13 | N317S, |
| 339 | 13 | |
| 316 | 13 | |
| 340 | 13 | F340L, F340L, F340L, |
| 315 | 14 | |
| 341 | 14 | |
| 314 | 14 | G314S, |
| 342 | 14 | D342A, D342V, D342X, |
| 313 | 15 | |
| 343 | 15 | L343fsX, |