KCNH2 Variant M462R

Summary of observed carriers, functional annotations, and structural context for KCNH2 M462R. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

20%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

M462R has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 0% of WT with a standard error of 7%. 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 (%)
-5.227 0.992 -2 0.963 50

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 M462R.
Neighbour residue Distance (Å) Observed variants
462 0 M462Ins,
461 5
465 5
463 6 F463L, F463L, F463L,
459 6
458 7
466 7 D466E, D466E,
464 7 I464X,
417 7
410 7 W410X,
460 8 D460fsX,
414 8 I414fsX,
413 8 L413P,
469 10
467 10
457 10 L457P,
531 10 R531W, R531Del, R531Q,
468 10 L468F, L468X, L468R,
418 11
456 11 D456Y,
416 11
505 11 A505V,
455 11
534 11 R534C
411 11
420 12 Y420C,
504 12 A504V,
421 12 T421fsX, T421M,
415 12
470 12 N470D,
407 12
406 12
528 13 R528W, R528X, R528P,
409 13 V409M, V409L, V409L,
501 13 D501N, D501H, D501Y,
454 13
419 14
507 14 P507S, P507L,
502 14 M502I, M502I, M502I,
412 14 W412X,
408 15
506 15 I506V,
538 15
453 15