KCNH2 Variant W497C

Summary of observed carriers, functional annotations, and structural context for KCNH2 W497C. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

16%

1/11 effective observations

Total carriers

1

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

W497C is present in 1 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 24% 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 (%)
-12.18 1.0 -3 0.945 76

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 – 1 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 W497C.
Neighbour residue Distance (Å) Observed variants
497 0 W497L, W497X,
496 5
537 5 R537W,
500 7 I500Del,
501 7 D501N, D501H, D501Y,
533 7
493 8 Y493H, Y493C, Y493F, Y493Ins,
499 8
498 8
534 8 R534C,
536 9 A536X,
492 9 H492Y,
495 9 K495X,
538 9
530 11
470 11 N470D,
535 11 V535M,
502 11 M502I, M502I, M502I,
494 11 F494Del,
532 12
467 12
503 12
475 13 Y475C, Y475Del,
466 13 D466E, D466E,
539 13
504 13 A504V,
490 13 A490T, A490P,
531 13 R531W, R531Del, R531Q,
471 13 F471X,
491 13 V491I,
489 14 I489F, I489I,
476 14 V476I,
463 14 F463L, F463L, F463L,
540 14 D540fsX
473 14 T473P,
411 15
477 15
505 15 A505V,
414 15 I414fsX,