KCNH2 Variant L417M

Summary of observed carriers, functional annotations, and structural context for KCNH2 L417M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

17%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L417M has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 124% of WT with a standard error of 10%. 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 (%)
-1.903 0.994 2 0.869 81

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 L417M.
Neighbour residue Distance (Å) Observed variants
417 0
418 5
416 5
414 5 I414fsX,
459 6
413 6 L413P,
420 6 Y420C,
415 7
419 7
421 7 T421fsX, T421M,
463 7 F463L, F463L, F463L,
462 7 M462Ins,
531 8 R531W, R531Del, R531Q,
410 9 W410X,
458 9
460 10 D460fsX,
422 10 A422T,
534 10 R534C,
456 10 D456Y,
455 10
411 10
532 10
466 10 D466E, D466E,
461 11
528 11 R528W, R528X, R528P,
424 11
423 11
535 11 V535M,
412 11 W412X,
465 12
425 12
504 12 A504V,
529 12
457 12 L457P,
464 12 I464X,
409 13 V409M, V409L, V409L,
542 13
538 13
533 13
530 13
505 13 A505V,
501 13 D501N, D501H, D501Y,
555 14
559 14 L559F, L559H
407 14
452 14
467 14
454 14
527 14
552 14 L552S,
551 14 F551L, F551L, F551L,
408 14
453 15
469 15
426 15 P426H,
537 15 R537W,
536 15 A536X,