KCNH2 Variant M574L

Summary of observed carriers, functional annotations, and structural context for KCNH2 M574L. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

12%

90% CI: 1.3% – 31.0%

1/11 effective observations

Total carriers

1

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

M574L is present in 1 alleles in gnomAD. This residue resides in a Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 105% 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 (%)
-0.954 0.012 1 0.609 42

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 – 1 1 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 M574L.
Neighbour residue Distance (Å) Observed variants
574 0 M574L, M574V, M574L,
573 5
570 5
575 6 E575K,
572 6 G572S, G572R, G572C, G572D,
571 7 I571L, I571V,
576 8
569 9 Y569H, Y569C, Y569X,
430 10
567 10 I567T, I567M,
636 11
577 11
429 12 A429P, A429V,
568 12 W568C, W568C,
431 12 F431L, F431L, F431L,
523 12
566 12 C566S, C566R, C566G, C566S, C566F,
586 12 L586M,
637 12 E637K, E637G, E637X,
585 13 W585C, W585C,
432 13
634 13 T634P, T634A, T634S, T634S, T634I,
522 13 G522E,
584 14 G584S, G584R, G584C,
640 14 F640L, F640V, F640Del, F640L, F640L
565 14
610 14
520 14
587 14
635 15 N635I,
583 15 I583V,
426 15 P426H,