KCNH2 Variant L415M

Summary of observed carriers, functional annotations, and structural context for KCNH2 L415M. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

15%

1/10 effective observations

Total carriers

0

0 LQT2 · 0 unaffected

Functional studies

0

Publications with functional data

L415M has not been reported in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 70% of WT with a standard error of 9%. 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 0.989 2 0.846 49

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 L415M.
Neighbour residue Distance (Å) Observed variants
415 0
416 5
414 5 I414fsX,
418 5
412 6 W412X,
419 6
535 7 V535M,
542 7
417 7
413 7 L413P,
411 7
552 8 L552S,
532 9
538 9
551 9 F551L, F551L, F551L,
534 9 R534C,
555 9
410 10 W410X,
421 10 T421fsX, T421M,
539 11
409 11 V409M, V409L, V409L,
536 11 A536X,
548 11
422 11 A422T,
541 11 R541C, R541H,
420 11 Y420C,
531 11 R531W, R531Del, R531Q,
463 11 F463L, F463L, F463L,
408 11
533 11
556 11
559 12 L559F, L559H
537 12 R537W,
549 12 V549M,
462 12 M462Ins,
459 12
543 12 S543fsX,
407 12
466 12 D466E, D466E,
423 12
540 13 D540fsX,
553 13 L553V,
529 14
545 14
544 14 E544A, E544fsX,
550 14
547 14 A547T,
558 14 A558P, A558E, A558V,
530 14
424 14
554 14
501 15 D501N, D501H, D501Y,