KCNH2 Variant I506M

Summary of observed carriers, functional annotations, and structural context for KCNH2 I506M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

I506M 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: 53% of WT with a standard error of 17%. 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 (%)
-2.805 0.962 1 0.857 22

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 I506M.
Neighbour residue Distance (Å) Observed variants
506 0 I506V,
505 4 A505V,
507 4 P507L, P507S,
503 5
504 6 A504V,
508 6
502 6 M502I, M502I, M502I,
527 8
528 9 R528P, R528W, R528X,
460 9 D460fsX,
524 9
464 9 I464X,
531 10 R531Q, R531W, R531Del,
501 10 D501H, D501N, D501Y,
525 10 K525N, K525N,
463 11 F463L, F463L, F463L,
530 11
500 11 I500Del,
498 11
499 11
467 11
526 12
509 12 D509N,
510 12
461 12
457 13 L457P,
459 13
529 13
456 14 D456Y,
522 14 G522E,
465 14
466 14 D466E, D466E,
534 14 R534C,
523 14
521 14
421 14 T421fsX, T421M,
425 15
462 15 M462Ins,
468 15 L468R, L468F, L468X,