KCNH2 Variant W412S

Summary of observed carriers, functional annotations, and structural context for KCNH2 W412S. 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

W412S has not been reported in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 31% of WT with a standard error of 13%. 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 (%)
-13.323 0.995 -3 0.894 17

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 W412S.
Neighbour residue Distance (Å) Observed variants
412 0 W412X,
542 5
411 6
415 6
409 6 V409M, V409L, V409L,
408 7
413 7 L413P,
541 7 R541C, R541H,
414 8 I414fsX,
416 8
548 9
545 9
410 9 W410X,
544 10 E544A, E544fsX,
538 10
551 10 F551L, F551L, F551L,
407 10
535 10 V535M,
552 10 L552S,
543 10 S543fsX,
540 11 D540fsX,
539 11
417 11
418 11
549 11 V549M,
547 12 A547T,
419 12
405 12
406 12
546 12
3 12
404 13
555 13
534 13 R534C,
536 13 A536X,
550 14
537 14 R537W,
532 14
466 14 D466E, D466E,
462 14 M462Ins,
553 15 L553V
402 15 H402R,