KCNH2 Variant M502L

Summary of observed carriers, functional annotations, and structural context for KCNH2 M502L. 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

M502L 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: 119% of WT with a standard error of 4%. 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 (%)
-2.072 0.0 2 0.475 19

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 M502L.
Neighbour residue Distance (Å) Observed variants
502 0 M502I, M502I, M502I,
503 4
501 5 D501Y, D501H, D501N,
505 5 A505V,
504 5 A504V,
498 5
499 6
500 6 I500Del,
506 6 I506V,
467 8
530 9
464 9 I464X,
531 9 R531W, R531Del, R531Q,
527 10
493 10 Y493H, Y493F, Y493Ins, Y493C,
463 10 F463L, F463L, F463L,
534 10 R534C,
507 10 P507L, P507S,
496 11
494 11 F494Del,
466 11 D466E, D466E,
497 11 W497X, W497L,
533 11
528 12 R528P, R528W, R528X,
470 12 N470D,
468 12 L468F, L468R, L468X,
460 12 D460fsX,
471 12 F471X,
508 12
465 13
537 13 R537W,
529 13
495 13 K495X,
524 14
526 14
461 14
532 14
469 14
490 14 A490T, A490P,
462 14 M462Ins,
459 15
525 15 K525N, K525N,