KCNH2 Variant S404R

Summary of observed carriers, functional annotations, and structural context for KCNH2 S404R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

16%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

S404R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 102% of WT with a standard error of 10%. 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 (%)
-4.758 0.937 -1 0.948 52

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 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 S404R.
Neighbour residue Distance (Å) Observed variants
404 0
405 4
403 5
401 5
407 6
406 6
408 6
402 7 H402R,
400 8 I400N,
409 9 V409M, V409L, V409L,
474 10 T474I,
541 10 R541H, R541C,
473 10 T473P,
411 10
5 10
410 11 W410X,
3 11
399 11
469 12
412 13 W412X,
470 13 N470D,
6 14 G6R,
538 14
544 14 E544A, E544fsX,
476 14 V476I,
482 14 V482A,
398 14 W398X, W398L,
475 14 Y475C, Y475Del,
413 14 L413P,
472 14 R472X, R472C,
484 14
542 14
695 15
540 15 D540fsX,
466 15 D466E, D466E,
414 15 I414fsX,
4 15
483 15 V483I,
691 15